Tiotropium Respimat inhaler and the risk of death in COPD Wise, Robert A; Anzueto, Antonio; Cotton, Daniel ...
New England journal of medicine/The New England journal of medicine,
10/2013, Volume:
369, Issue:
16
Journal Article
Peer reviewed
Open access
Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials ...involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo.
In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 μg or 5 μg, as compared with tiotropium HandiHaler at a once-daily dose of 18 μg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 μg or 2.5 μg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 μg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease.
During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval CI, 0.84 to 1.09; Respimat at a dose of 2.5 μg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups.
Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.).
Although commonly used as the primary outcome measure of clinical trials in pulmonary arterial hypertension (PAH), the minimal important difference (MID) of the 6-minute walk test (6MWT) has not been ...well defined for this population of patients.
To estimate the MID in the 6MWT in patients with PAH.
Study subjects from the clinical trial of tadalafil in PAH, a 16-week, parallel-group, randomized clinical trial of patients who were treatment naive or on background therapy with an endothelin receptor antagonist, were eligible. 6MWT was performed using a standardized protocol. Distributional and anchor-based methods were used to estimate the MID; the latter method used the Physical Component Summary Score (PCS) of the Medical Outcomes Study 36-item short form (SF-36).
Four hundred five subjects were analyzed. Domains of the SF-36 were weakly to modestly associated with 6MWT. Change in the PCS of the SF-36 was most strongly associated with change in 6MWT (r = 0.40, P < 0.001) and thus was selected as the anchor for subsequent anchor-based analyses. Distributional analyses yielded estimates of the MID ranging from 25.1 to 38.5 m, whereas anchor-based analyses yielded an estimate of 38.6 m.
Using both distributional and anchor-based methods, the estimated consensus MID in the 6MWT for PAH is approximately 33 m. These results have important implications for (1) assessing treatment responses from clinical trials and metaanalyses of specific PAH therapy, and (2) sample size calculations for future study design.
The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β
-agonist (LABA), as ...compared with dual therapy (either inhaled glucocorticoid-LABA or LAMA-LABA), are uncertain.
In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate-vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium-vilanterol (at doses of 62.5 μg and 25 μg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment.
The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval CI, 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium-vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium-vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium-vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001).
Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate-vilanterol or umeclidinium-vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium-vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513 .).
COPD patients have high pulmonary and systemic oxidative stress that correlates with severity of disease. Sulforaphane has been shown to induce expression of antioxidant genes via activation of a ...transcription factor, nuclear factor erythroid-2 related factor 2 (Nrf2).
This parallel, placebo-controlled, phase 2, randomized trial was conducted at three US academic medical centers. Patients who met GOLD criteria for COPD and were able to tolerate bronchoscopies were randomly assigned (1:1:1) to receive placebo, 25 μmoles, or 150 μmoles sulforaphane daily by mouth for four weeks. The primary outcomes were changes in Nrf2 target gene expression (NQ01, HO1, AKR1C1 and AKR1C3) in alveolar macrophages and bronchial epithelial cells. Secondary outcomes included measures of oxidative stress and airway inflammation, and pulmonary function tests.
Between July 2011 and May 2013, 89 patients were enrolled and randomized. Sulforaphane was absorbed in the patients as evident from their plasma metabolite levels. Changes in Nrf2 target gene expression relative to baseline ranged from 0.79 to 1.45 and there was no consistent pattern among the three groups; the changes were not statistically significantly different from baseline. Changes in measures of inflammation and pulmonary function tests were not different among the groups. Sulforaphane was well tolerated at both dose levels.
Sulforaphane administered for four weeks at doses of 25 μmoles and 150 μmoles to patients with COPD did not stimulate the expression of Nrf2 target genes or have an effect on levels of other anti-oxidants or markers of inflammation.
Clinicaltrials.gov: NCT01335971.
Comorbidities impact a large proportion of patients with chronic obstructive pulmonary disease (COPD), with over 80% of patients with COPD estimated to have at least one comorbid chronic condition. ...Guidelines for the treatment of COPD are just now incorporating comorbidities to their management recommendations of COPD, and it is becoming increasingly clear that multimorbidity as well as specific comorbidities have strong associations with mortality and clinical outcomes in COPD, including dyspnea, exercise capacity, quality of life, healthcare utilization, and exacerbation risk. Appropriately, there has been an increased focus upon describing the burden of comorbidity in the COPD population and incorporating this information into existing efforts to better understand the clinical and phenotypic heterogeneity of this group. In this article, we summarize existing knowledge about comorbidity burden and specific comorbidities in COPD, focusing on prevalence estimates, association with outcomes, and existing knowledge about treatment strategies.
Background Information comparing subjective and objective measurements of adherence to study medications and the effects of adherence on treatment-related differences in asthma clinical trials are ...limited. Objective We sought to compare subjective and objective measurements of children’s adherence to inhaled corticosteroids or placebo and to determine whether adherence to study medications modified treatment-related differences in outcomes. Methods In an ancillary study conducted in 3 of 8 Childhood Asthma Management Program Clinical Centers, adherence was assessed by using self-reported and objective data in 5- to 12-year-old children with mild or moderate asthma who were randomly assigned to 200 μg of inhaled budesonide twice per day (n = 84) or placebo (n = 56) for 4 years. The κ statistic was used to evaluate agreement between self-reported adherence (daily diary cards) and objectively measured adherence (number of doses left in study inhalers). Multivariable analyses were used to determine whether adherence to study treatment modified treatment-related differences in outcomes. Results Adherence of less than 80% was seen in 75% of 140 children when adherence was measured objectively but only in 6% of children when measured by means of self-report. There was poor agreement between objective and subjective measurements of adherence of at least 80% (κ = 0.00; 95% CI, −0.05 to 0.04); self-reported adherence over the 4-year period generally overestimated objectively measured adherence (93.6% vs 60.8%, P < .0001). There was little evidence to indicate that adherence modified treatment-related differences in outcomes. Conclusion Researchers should use objective rather than self-reported adherence data to identify clinical trial participants with low levels of adherence to study treatment.
Cigarette smoking is the strongest risk factor for COPD. Smoking burden is frequently measured in pack-years, but the relative contribution of cigarettes smoked per day versus duration towards the ...development of structural lung disease, airflow obstruction and functional outcomes is not known.
We analysed cross-sectional data from a large multicentre cohort (COPDGene) of current and former smokers. Primary outcome was airflow obstruction (FEV
/FVC); secondary outcomes included five additional measures of disease: FEV
, CT emphysema, CT gas trapping, functional capacity (6 min walk distance, 6MWD) and respiratory morbidity (St George's Respiratory Questionnaire, SGRQ). Generalised linear models were estimated to compare the relative contribution of each smoking variable with the outcomes, after adjustment for age, race, sex, body mass index, CT scanner, centre, age of smoking onset and current smoking status. We also estimated adjusted means of each outcome by categories of pack-years and combined groups of categorised smoking duration and cigarettes/day, and estimated linear trends of adjusted means for each outcome by categorised cigarettes/day, smoking duration and pack-years.
10 187 subjects were included. For FEV
/FVC, standardised beta coefficient for smoking duration was greater than for cigarettes/day and pack-years (P<0.001). After categorisation, there was a linear increase in adjusted means FEV
/FVC with increase in pack-years (regression coefficient β=-0.023±SE0.003; P=0.003) and duration over all ranges of smoking cigarettes/day (β=-0.041±0.004; P<0.001) but a relatively flat slope for cigarettes/day across all ranges of smoking duration (β=-0.009±0.0.009; P=0.34). Strength of association of duration was similarly greater than pack-years for emphysema, gas trapping, FEV
, 6MWD and SGRQ.
Smoking duration alone provides stronger risk estimates of COPD than the composite index of pack-years.
Post-results; NCT00608764.
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