T Glaab

Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD

BACKGROUND Treatment 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. METHODS In 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. RESULTS A 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. CONCLUSIONS These 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.).

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

BACKGROUND There 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. METHODS Analyses 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. RESULTS Of 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. CONCLUSIONS This analysis presented a marked impact of season on exacerbation outcomes, antibiotic treatment, timing of second exacerbations, and all-cause mortality.

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.

Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial

BACKGROUND The effect of β2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol. METHODS We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381. FINDINGS 5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0·0130) and Gly16Gly (p=0·0018) genotypes (proportion of patients with at least one exacerbation was 32·3% in Arg16Arg, 39·8% in Arg16Gly, and 42·1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0·0164; Arg16Arg p=0·0316; proportion of patients with at least one exacerbation was 28·3% in Arg16Arg, 31·6% in Arg16Gly, and 39·2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0·0198; not Arg16Gly p=0·64; proportion of patients with at least one exacerbation was 35·9% in Arg16Arg, 46·7% in Arg16Gly, and 44·8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events. INTERPRETATION Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting β-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of β-adrenergic polymorphisms and their association with clinical features of COPD. FUNDING Boehringer Ingelheim and Pfizer.

Study design considerations in a large COPD trial comparing effects of tiotropium with salmeterol on exacerbations

Currently available long-acting inhaled bronchodilators (tiotropium, salmeterol, formoterol) have demonstrated beneficial effects on exacerbations in placebo-controlled trials. However, there have been no direct comparisons of these drugs with exacerbations as the primary outcome and consequently COPD treatment guidelines do not indicate a preference for either bronchodilator. Therefore, an international, randomized, double-blind, double-dummy, parallel-group clinical trial has been designed to investigate the comparative efficacy of 2 long-acting bronchodilators tiotropium 18 μg daily and salmeterol 50 μg bid on exacerbations. The trial will include at least 6800 randomized patients with diagnosis of COPD, ≥ 10 pack-year history of smoking, post-bronchodilator FEV1 ≤ 70% predicted, and a history of exacerbations in the previous year. The primary endpoint is time to first COPD exacerbation. Secondary endpoints include number of exacerbations and time to premature discontinuation of trial medication. The trial has been designed to address several of the challenges in studying exacerbations in a controlled trial by a symptom and event-based definition of exacerbations, frequent follow-up contacts, selection of time to first event as the primary endpoint and using exposure adjusted analysis when examining number of events. Other challenges in designing exacerbation trials such as differential discontinuation and follow-up of discontinued patients are discussed.

Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naïve patients

The objective of this study was to investigate the effect of tiotropium compared with salmeterol on exacerbations in patients with moderate (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II) chronic obstructive pulmonary disease (COPD) and those naïve to maintenance respiratory therapy in the 1-year Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD(®)) trial (NCT00563381). Time to first exacerbation (primary endpoint) and rates of exacerbations were analyzed using exploratory Cox and Poisson regression (adjusting for time on treatment). Of 7376 randomized patients, 3614 were GOLD stage II (tiotropium n = 1781; salmeterol n = 1833) and 1343 were maintenance therapy naïve (tiotropium n = 672; salmeterol n = 671). Tiotropium significantly increased time to first exacerbation vs. salmeterol in GOLD stage II patients (hazard ratio [HR], 0.88; 95% confidence interval [CI]: 0.79-0.99; p = 0.028) and maintenance therapy naïve patients (HR, 0.79; 95% CI, 0.65-0.97; p = 0.028). Annual exacerbation rates were also significantly lower with tiotropium in the maintenance naïve subgroup compared with salmeterol (rate ratio [RR], 0.77; 95% CI, 0.63-0.94; p = 0.012). In the GOLD stage II subgroup, the rate of hospitalized exacerbations per year was significantly lower with tiotropium than with salmeterol (RR, 0.70; 95% CI, 0.57-0.85; p < 0.001); tiotropium also significantly prolonged time to first hospitalized exacerbation versus salmeterol in this subgroup (HR, 0.66; 95% CI, 0.48-0.91; p = 0.012). In conclusion, results from this prespecified subgroup analysis support the selection of tiotropium as first-choice maintenance therapy for patients with GOLD stage II COPD.

Preselection of patients at risk for COPD by two simple screening questions

BACKGROUND The Burden of Obstructive Lung Disease study showed that in Germany, to confirm the diagnosis of chronic obstructive lung disease (COPD) in one subject, eight people ≥ 40 years of age have to be screened. The number-needed-to-screen (NNS) increased to 18 for identifying a patient with COPD ≥ GOLD stage II. These high numbers limit the cost-effectiveness of COPD screening by population spirometry. We investigated in a primary care setting whether using two simple questions regarding smoking status and presence of cough and/or dyspnea may help to preselect patients for proper diagnosis of COPD. METHODS A total of 1088 patients aged ≥ 40 yrs without a history of chronic lung disease, who were either current or ex-smokers and complained of cough and/or dyspnea, were examined by respiratory physicians. Spirometry was carried out to confirm COPD diagnosis and severity. RESULTS A total of 61.6% of patients were male. Mean smoking history was 31.8 pack-yrs. In 516 patients (47.4%), a diagnosis of COPD was confirmed. Among these, 379 (34.8% of total) had at least GOLD stage II COPD, while 89 (8.2% of total) had advanced disease (GOLD stages III/IV). COPD prevalence was significantly associated with age and the extent of cigarette smoke exposure. CONCLUSIONS Two questions regarding smoking status and presence of cough and/or dyspnea enabled general practitioners to select patients at risk for COPD for subsequent spirometry. This preselection reduced the NNS to 2.1 for identifying a COPD patient, and to 2.9 for identifying a patient of at least GOLD stage II.

COPD-Screening in der hausärztlichen Praxis mit einem Lungenfunktions-Schnellmessgerät

BACKGROUND Screening measures can facilitate the diagnosis of chronic obstructive pulmonary disease (COPD) and help save costs and time. We examined whether use of a lung function screener (Vitalograph copd-6™) can help general practitioners to identify patients at risk for COPD. METHODS In 17,856 patients aged > 40 years (smokers/ex-smokers with cough and/or exertional dyspnoea) general practitioners measured prebronchodilator FEV1 [% of predicted] and FEV1/FEV6 with the lung function screening device. In addition, the general practitioners completed a questionnaire on symptoms, history and planned measures and estimated whether or not the patient was at risk for COPD. RESULTS In 2927 patients (16.7 %) an FEV1/FEV6 < 70 % was measured; 88.2 % of these were classed by the doctors as being at risk for COPD. The total number of all patients with suspected COPD was considerably greater (10,000; 56 % of the total population); in only 25.3 % was an FEV1/FEV6 < 70 % documented. Compared with patients without a suspicion of COPD, patients judged to be at risk for COPD in spite of an FEV1/FEV6 ≥ 70 % were more often male, had more cigarette pack years and more often had dyspnoea, but less often cough, as main symptom. They had more concomitant diseases and previous hospitalisations, more prescriptions for bronchodilators, glucocorticoids and antibiotics in the past year and lower FEV1 values. In 61.3 % of the patients with suspected COPD the general practitioners planned further evaluation by spirometry, in 39.9 % referral to a pulmonologist as alternative or additional procedures were suggested. CONCLUSION Most patients with an FEV1/FEV6 < 70 % measured with the lung function screener Vitalograph copd-6™ were classed by the general practitioners as being at risk for COPD. Even in patients with unremarkable FEV1/FEV6 values the diagnosis of suspected COPD was often made if clinical signs or symptoms or a reduced FEV1 pointed to such a suspicion.

Detection of air trapping in chronic obstructive pulmonary disease by low frequency ultrasound

BackgroundSpirometry is regarded as the gold standard for the diagnosis of COPD, yet the condition is widely underdiagnosed. Therefore, additional screening methods that are easy to perform and to interpret are needed. Recently, we demonstrated that low frequency ultrasound (LFU) may be helpful for monitoring lung diseases. The objective of this study was to evaluate whether LFU can be used to detect air trapping in COPD. In addition, we evaluated the ability of LFU to detect the effects of short-acting bronchodilator medication.MethodsSeventeen patients with COPD and 9 healthy subjects were examined by body plethysmography and LFU. Ultrasound frequencies ranging from 1 to 40 kHz were transmitted to the sternum and received at the back during inspiration and expiration. The high pass frequency was determined from the inspiratory and the expiratory signals and their difference termed ΔF. Measurements were repeated after inhalation of salbutamol.ResultsWe found significant differences in ΔF between COPD subjects and healthy subjects. These differences were already significant at GOLD stage 1 and increased with the severity of COPD. Sensitivity for detection of GOLD stage 1 was 83% and for GOLD stages worse than 1 it was 91%. Bronchodilator effects could not be detected reliably.ConclusionsWe conclude that low frequency ultrasound is cost-effective, easy to perform and suitable for detecting air trapping. It might be useful in screening for COPD.Trial RegistrationClinicalTrials.gov: NCT01080924

Is There a Role for Antiinflammatory Treatment in COPD

By definition, chronic obstructive pulmonary disease (COPD) is associated with an abnormal inflammatory response of affected lungs. Therefore, the search for an effective anti-inflammatory therapy for this debilitating disease is intense. However, to date, there is no such anti-inflammatory treatment for COPD. While there are some modest effects of inhaled corticosteroids on selected clinical endpoints in COPD, it remains to be proven that the observed effects are due to changes in the underlying inflammation, in particular since relevant clinical endpoints of COPD can be significantly improved by treatments not targeting inflammation. Therefore, it appears justified to reconsider the present knowledge about any linkage of local and systemic inflammation and clinical features of COPD, including lung function, exacerbations, disease progression, and mortality. Any such link needs to be carefully established before future anti-inflammatory therapies for COPD are developed and investigated in clinical trials, in particular since proof-of-concept trials aiming merely at inflammatory markers in COPD may not be predictive of clinical success or failure. The present review summarizes current knowledge about the role of inflammation in COPD, and critically analyzes results from clinical trials with inhaled corticosteroids and phosphodiesterase-4 inhibitors in COPD, the two classes of putative antiinflammatory agents with the richest body of evidence from controlled studies.