Evidence is weak for the ability of long-term non-invasive positive pressure ventilation (NPPV) to improve survival in patients with stable hypercapnic chronic obstructive pulmonary disease (COPD). ...Previous prospective studies did not target a reduction in hypercapnia when adjusting ventilator settings. This study investigated the effect of long-term NPPV, targeted to markedly reduce hypercapnia, on survival in patients with advanced, stable hypercapnic COPD.
This investigator-initiated, prospective, multicentre, randomised, controlled clinical trial enrolled patients with stable GOLD stage IV COPD and a partial carbon dioxide pressure (PaCO2) of 7 kPa (51.9 mm Hg) or higher and pH higher than 7.35. NPPV was targeted to reduce baseline PaCO2 by at least 20% or to achieve PaCO2 values lower than 6.5 kPa (48.1 mm Hg). Patients were randomly assigned (in a 1:1 ratio) via a computer-generated randomisation sequence with a block size of four, to continue optimised standard treatment (control group) or to receive additional NPPV for at least 12 months (intervention group). The primary outcome was 1-year all-cause mortality. Analysis was by intention to treat. The intervention was unblinded, but outcome assessment was blinded to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT00710541.
Patients were recruited from 36 respiratory units in Germany and Austria, starting on Oct 29, 2004, and terminated with a record of the vital status on July 31, 2011. 195 patients were randomly assigned to the NPPV group (n=102) or to the control group (n=93). All patients from the control group and the NPPV group were included in the primary analysis. 1-year mortality was 12% (12 of 102 patients) in the intervention group and 33% (31 of 93 patients) in the control group; hazard ratio 0.24 (95% CI 0.11-0.49; p=0.0004). 14 (14%) patients reported facial skin rash, which could be managed by changing the type of the mask. No other intervention-related adverse events were reported.
The addition of long-term NPPV to standard treatment improves survival of patients with hypercapnic, stable COPD when NPPV is targeted to greatly reduce hypercapnia.
German Lung Foundation; ResMed, Germany; Tyco Healthcare, Germany; and Weinmann, Germany.
Many patients with chronic obstructive pulmonary disease (COPD) receive inhaled corticosteroids (ICSs) without a clear indication, and thus, the impact of ICS withdrawal on disease control is of ...great interest. DACCORD is a prospective, noninterventional 2-year study in the primary and secondary care throughout Germany. A subgroup of patients were taking ICS prior to entry - 1,022 patients continued to receive ICS for 2 years; physicians withdrew ICS on entry in 236 patients. Data from these two subgroups were analyzed to evaluate the impact of ICS withdrawal. Patients aged ≥40 years with COPD, initiating or changing COPD maintenance medication were recruited, excluding patients with asthma. Demographic and disease characteristics, prescribed COPD medication, COPD Assessment Test, exacerbations, and lung function were recorded. There were few differences in baseline characteristics; ICS withdrawn patients had shorter disease duration and better lung function, with 74.2% of ICS withdrawn patients not exacerbating, compared with 70.7% ICS-continued patients. During Year 1, exacerbation rates were 0.414 in the withdrawn group and 0.433 in the continued group. COPD Assessment Test total score improved from baseline in both groups. These data suggest that ICS withdrawal is possible with no increased risk of exacerbations in patients with COPD managed in the primary and secondary care.
No observational studies have evaluated the "real-world" effectiveness of dual bronchodilation comprising a long-acting β
-agonist plus a long-acting muscarinic antagonist vs that of triple therapy ...(long-acting β
-agonist plus long-acting muscarinic antagonist plus inhaled corticosteroid) in COPD.
DACCORD is a non-interventional, observational clinical study that recruited patients following COPD maintenance therapy initiation or change in maintenance therapy between or within therapeutic class. Given the non-interventional nature of the study, the decision to initiate or change medication had to be made by the patients' physicians prior to inclusion in DACCORD. We used a matched-pairs analysis to compare disease progression in two patient groups: those receiving dual bronchodilation vs those receiving triple therapy (each group n=1,046).
In two subgroups of patients matched according to a broad range of demographic and disease characteristics, over 1 year, fewer patients receiving dual bronchodilation exacerbated than those receiving triple therapy (15.5% vs 26.6%;
<0.001), with a greater improvement from baseline in COPD Assessment Test total score at 1 year (mean±SD -2.9±5.8 vs -1.4±5.5;
<0.001). When analyzed according to prior therapy, the highest rate of exacerbations was in patients on triple therapy prior to the study who remained on triple therapy. Those changing from mono-bronchodilator to dual bronchodilation had the greatest COPD Assessment Test total score improvement.
In this "real-life" cohort of patients with COPD, most of whom had not exacerbated in the 6 months prior to entry, triple therapy did not seem to improve outcomes compared with dual bronchodilation in terms of either exacerbations or health status. Our analyses clearly demonstrate the potential impact of prior medication on study results, something that should be taken into account when interpreting the results even of controlled clinical trials.
Real-word evidence on the effectiveness of switching from dual therapies or triple therapies (multiple inhalers) to extrafine single-inhaler triple therapy (efSITT), which consists of the inhaled ...corticosteroid (ICS) beclomethasone, the long-acting β
-agonist (LABA) formoterol and the long-acting muscarinic antagonist (LAMA) glycopyrronium, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) is limited. The impact of switching to efSITT on health-related quality of life (HRQoL), COPD specific symptoms, lung function and treatment adherence were assessed in routine clinical care.
Patients were recruited at 148 sites in Germany between 2017 and 2020 in this multicenter, non-interventional observational study. Demographics, clinical data and treatment history were collected at baseline. HRQoL (measured by COPD Assessment Test CAT), lung function and adherence (measured by Test of Adherence to Inhalers TAI) were assessed at baseline and after six months. Descriptive analyses were conducted by prior treatment and GOLD groups as well as for the overall population.
55.1% of the 2623 included patients were male. Mean age was 65.8 years. 57.5% of the patients were previously treated with ICS+LABA+LAMA (multiple inhalers), 23.9% with ICS/LABA (single or two inhalers) and 18.6% with LAMA/LABA (single or two inhalers). After six months, largest mean improvements in the total CAT score were observed in the ICS/LABA (-3.9) and LAMA/LABA (-3.9) prior treatment groups as well as in patients in GOLD group B (-2.9). In the overall population, the CAT items for cough, phlegm, and dyspnea decreased on average by -0.4 points each. After six months, FEV
increased by 2.0 percentage points in relation to predicted values. The percentages of measured sRtot and RV of predicted values decreased by 24.5 and 4.4 percentage points, respectively. The percentage of patients with good adherence increased from 67.8% to 76.5%.
Treatment switch to efSITT resulted in an improvement of HRQoL, COPD specific symptoms, lung function parameters and adherence under real-world conditions.
The autonomic nervous system may be disturbed in chronic respiratory failure. We tested the hypothesis that there is increased sympathetic activity in patients with chronic hypoxemia. Furthermore, we ...examined the effect of short-term oxygen on muscle sympathetic nerve activity (MSNA) in these patients. We performed microneurography of the peroneal nerve in 11 patients with hypoxemia due to chronic obstructive pulmonary disease (COPD, n = 6) or lung fibrosis (n = 5) and in 11 healthy subjects matched for age and sex. MSNA was measured during normal breathing in all subjects. In eight patients and in seven control subjects, MSNA was also measured during nasal oxygen (4 L/min). MSNA was higher in the patients with chronic respiratory failure compared with the healthy subjects during normal breathing (61 +/- 5 versus 34 +/- 2 bursts/min, mean +/- SEM; p = 0.0002, paired t test). During oxygen administration, MSNA decreased from 63 +/- 6 to 56 +/- 6 bursts/min in the patients (p = 0.0004, ANOVA); there was no change in sympathetic activity in the control subjects. For the first time, there is direct evidence of marked sympathetic activation in patients with chronic respiratory failure. This is partly explained by arterial chemoreflex activation and may play an important role in the pathogenesis of the disease.
Randomized interventional trials generally recruit highly selected patients. In contrast, long-term, noninterventional studies can reflect standard of care of real-life populations. DACCORD (Die ...ambulante Versorgung mit langwirksamen Bronchodilatatoren: COPD-Register in Deutschland Outpatient Care With Long-Acting Bronchodilators: COPD Registry in Germany) is an ongoing observational study, conducted in primary and secondary care in Germany, aiming to describe the impact of disease and treatments on real-life patients with chronic obstructive pulmonary disease (COPD).
Patients had a clinical and spirometry diagnosis of COPD, were aged ≥40 years, and were initiating or changing COPD maintenance medication. The only exclusion criteria were asthma and participation in a randomized clinical trial. Exacerbation data were collected every 3 months. COPD medication, COPD Assessment Test, and forced expiratory volume in 1 second (FEV1) were recorded at the end of the 1 year period.
In the 6 months prior to baseline, 26.5% of the 3,974 patients experienced ≥1 exacerbation, compared with 26.1% over the 1-year follow-up (annualized rate 0.384). Importantly, only previous exacerbations and not poor lung function alone predicted an increased exacerbation risk. There was a general shift to lower disease severity from baseline to 1 year, predominantly as a consequence of a lower proportion of patients considered at high risk due to exacerbations. COPD Assessment Test mean change from baseline was -1.9, with 48.9% of patients reporting a clinically relevant improvement. Overall persistence to medication was high, with 77.2% of patients still receiving the same class of medication at 1 year.
DACCORD suggests that in clinical practice, the large majority of COPD patients are symptomatic but seldom exacerbate and that widely used tools and treatment recommendations do not reflect this fully.
Formoterol, a long-acting beta (2)-agonist with a rapid onset of bronchodilation, is available in various delivery devices. However, differences in the size and uniformity of drug particles generated ...by different devices may result in variable clinical effects. The present study compared in vitro the aerodynamic particle size distribution, emitted dose and device resistance of formoterol delivered via Foradil Aerolizer (Foradil P) with those a non-proprietary single-dose capsule inhaler (ratiopharm), using an 8-stage Andersen Cascade Impactor set at a flow of 60 L/min. Relative to the formoterol ratiopharm capsule inhaler, Foradil Aerolizer produced particles with a smaller mass median aerodynamic diameter (3.5 vs. 4.1 microm, p = 0.018) and a smaller measured particle diameter distribution (geometric standard deviation 2.2 vs. 2.5, p = 0.048). The Foradil Aerolizer produced a 44% higher fine particle dose than the single-dose capsule inhaler (2.6 vs. 1.8 microg, p = 0.0001). Although the single-dose capsule inhaler produced a higher total emitted dose than that from Foradil Aerolizer (11.2 vs. 10.0 microg, p = 0.155, not significant), the respirable fraction from Foradil Aerolizer was 58% higher (25.7 vs. 16.3%, p = 2 x 10(8)). Both devices had a similarly low airflow resistance. These relative particle size profiles suggest that the Aerolizer may provide a more clinically effective delivery of formoterol to the lungs at the high inspiratory flows such as are typically achieved using this device.
Summary Background Mouth occlusion pressure measurement is widely used for assessment of respiratory muscle function, particularly in patients with respiratory failure. However, its predictive value ...for long-term survival remains largely unexplored. Methods In 464 patients with chronic hypercapnic respiratory failure (CHRF) due to various underlying disorders and receiving non-invasive ventilation (NIV), maximal inspiratory mouth pressure (PImax ), mouth occlusion pressure at 100 ms during quiet breathing ( P0.1 ) and the ratio P0.1 /PImax were assessed prior to and after treatment including NIV. Baseline data and changes at follow-up were used to evaluate their predictive value for long-term survival. Results Overall, median (quartiles) P0.1 was 177.0 (109.2;287.0) %pred, PImax 35.0 (24.0;47.0) %pred, and P0.1 /PImax 564.0 (275.7;1082.3) %pred. In multivariate analyses, P0.1 was related to airflow obstruction, lung hyperinflation, haemoglobin (Hb) and leukocytes, and PImax to airflow obstruction and hyperinflation ( p <0.05 each). All-cause mortality during follow-up (median 31.6 months) was 31.5%. Survival was associated with age, body-mass index (BMI), lung function, leukocytes, Hb, PImax , P0.1 and P0.1 /PImax ( p <0.01 each, univariate). Among these multivariate Cox regression identified age, BMI, FEV1 , leukocytes and P0.1 /PImax as independent predictors ( p <0.05 each). Furthermore, the decrease of P0.1 /PImax at follow-up was associated with improved survival in patients with high baseline P0.1 /PImax (>50th or 75th percentile; p <0.05). Conclusions In patients with CHRF and current NIV therapy, P0.1 /PImax was an independent predictor of long-term survival, in addition to previously established risk factors. Moreover, a decrease in P0.1 /PImax after treatment including NIV was associated with an improved survival in patients with high baseline P0.1 /PImax values.
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