Evidence-Based Inhaler Therapy for COPD in 2018

See the winner of the 2018 Best of ATS Video Lecture Series: Penn PET Project: Evidence-Based Inhaler Therapy for #COPD

Triple versus Dual Inhaler Therapy in Patients with COPD - IMPACT Trial can change COPD Guidelines in 2019

The Informing the Pathway of COPD Treatment (IMPACT) trial, now reported in the The New England Journal of Medicine, aims to fill this gap with a report on the effectiveness of LAMA–LABA–inhaled glucocorticoid treatment, contained in a single inhaler, in COPD.

Background

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 β₂-agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid–LABA or LAMA–LABA), are uncertain.

Methods

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.

Results

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).

Conclusions

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.

full text:

http://www.nejm.org/doi/full/10.1056/NEJMoa1713901

Emerging biological therapies for treating eosinophilic COPD

In Pulmonary Pharmacology & Therapeutics was published meta-analysis by great Italian team on hot topic Emerging biological therapies for treating chronic obstructive pulmonary disease: A pairwise and network meta-analysis.

Inflammation in COPD is often corticosteroid resistant and, thus, alternative anti-inflammatory approaches are needed. Since it is still not clear whether blocking specific pro-inflammatory factors may provide clinical benefit in COPD, we have performed a meta-analysis to quantify the impact of monoclonal antibodies (mABs) targeting the cytokine/chemokine-mediated inflammation in COPD.

A pairwise and network meta-analyses were performed by extracting data from randomized clinical trials on COPD concerning the impact of mABs vs. placebo on the risk of exacerbation, forced expiratory volume in 1 s (FEV₁), and St. George's Respiratory Questionnaire (SGRQ).

Data on the interleukin (IL)-1β antagonist canakinumab, IL-1R1 antagonist MEDI8986, IL-5 antagonist mepolizumab, IL-5R antagonist benralizumab, IL-8 antagonist ABX-IL8, and TNF-α antagonist infliximab were found. Overall, mAB therapy had a moderate impact on the risk exacerbation, but not on FEV₁ and SGRQ. The pairwise meta-analysis performed in eosinophilic patients, and the network approach, indicated that mepolizumab elicited a beneficial effect against the risk of exacerbation, whereas benralizumab was more effective in improving both FEV₁ and SGRQ.

This study demonstrates that targeting the pathway activated by IL-5 may have a beneficial impact in eosinophilic COPD patients.

Full text:

https://www.sciencedirect.com/science/article/pii/S1094553918300579

Exacerbations of COPD: prevention is still actual in 2018!!

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. While COPD is a mainly chronic disease, a substantial number of patients suffer from exacerbations. Severe exacerbations are related to a significantly worse survival outcome. This review summarises the current knowledge on the different aspects of COPD exacerbations. The impact of risk factors and triggers such as smoking, severe airflow limitation, bronchiectasis, bacterial and viral infections and comorbidities is discussed. More severe exacerbations should be treated with β-agonists and anticholinergics as well as systemic corticosteroids. 

Antibiotic therapy should only be given to patients with presumed bacterial infection. Noninvasive ventilation is indicated in patients with respiratory failure. Smoking cessation is key to prevent further COPD exacerbations. Other aspects include choice of pharmacotherapy, including bronchodilators, inhaled corticosteroids, phosphodiesterase-4 inhibitors, long-term antibiotics and mucolytics. Better education and self-management as well as increased physical activity are important. Influenza and pneumococcal vaccination is recommended. Treatment of hypoxaemia and hypercapnia reduce the rate of COPD exacerbations, while most interventional bronchoscopic therapies increase exacerbation risk within the first months after the procedure.

The prevention of exacerbations is one of the most important treatment goals. To achieve that goal, patient education and smoking cessation programmes as well as patient-tailored pharmacological and nonpharmacological treatments are mandatory.

Full text:

http://err.ersjournals.com/content/27/147/170103

Dual LABA/LAMA bronchodilators in COPD: why? when? and how?

Dual LABA/LAMA bronchodilators in COPD: why? when? and how?

Still many questions in our real everyday practice!

Read Editorial in Expert Review of Respiratory Medicine by great Italian team conducted by professor Mario Cazzola. 

http://www.tandfonline.com/doi/abs/10.1080/17476348.2018.1442216

LABA/LAMA combinations induce bronchorelaxant synergistic interaction when the drugs mixture is well-balanced and administered at low isoeffective concentrations.
The overall approach of Drug Companies has been to combine in a FDC a LABA and a LAMA at the same doses for which the monocomponents were previously approved. Indeed, this practice does not permit to optimize the synergy in the final
LABA/LAMA FDCs. Conversely, dose-finding studies are required to identify the correct dose-ratio and establish the minimal doses for each monocomponent in the FDC leading to the greater synergism with regard to the improvement in lung
function, symptoms, and exacerbations.
Furthermore, although LABA/LAMA FDCs are characterized by an acceptable safety profile, the cardiovascular toxicity of LABAs and LAMAs may overlap. Thus, postmarketing surveillance and observational studies are needed to assess the real risk of rare, but potentially serious, cardiovascular adverse events associated with the dual bronchodilation therapy in COPD patients.

Full text:

http://www.tandfonline.com/doi/abs/10.1080/17476348.2018.1442216

COPD in 2018: syndrome or disease - first steps to new classification

New article from ERJ Open Research by Celli and Agusti is dedicated to hot topic in COPD: new classification with absolutely fresh approach!

Due to well-conducted epidemiological studies and advances in genetics, molecular biology, translational research, the advent of computed tomography of the lungs and bioinformatics, the diagnosis of chronic obstructive pulmonary disease (COPD) as a single entity caused by susceptibility to cigarette smoke is no longer tenable. Furthermore, the once-accepted concept that COPD results from a rapid and progressive loss of lung function over time is not true for a sizeable proportion of adults with the disease. Now we know that some genetic predisposition and/or different environmental interactions (nutritional, infectious, pollution and immunological) may negatively modulate post-natal lung development and lead to poorly reversible airflow limitation later in life, consistent with COPD.

 

We believe it is time to rethink the taxonomy of this disease based on the evidence at hand. To do so, we have followed the principles outlined in the 1980s by J.D. Scadding who proposed that diseases can be defined by four key characteristics: 1) clinical description (syndrome), 2) disorder of structure (morbid anatomy), 3) disorder of function (pathophysiology) and 4) causation (aetiology). 

Here, we propose a pragmatic approach to the taxonomy of COPD based on different processes that result in a similar syndromic presentation. It can accommodate changes over time, as the pathobiology that may lead to COPD expands. We hope that stakeholders in the field may find it useful to better define the patients now boxed into one single entity, so that specific studies can be designed and conducted for each type of COPDs.

Free full text:

http://openres.ersjournals.com/content/4/1/00132-2017

Pulmonary rehabilitation and cardiovascular risk in COPD: a systematic review (Free Full text from 2017 COPD Research and Practice)

Introduction

Pulmonary Rehabilitation (PR) is an effective intervention in COPD however the value of PR in reducing cardiovascular risk in COPD (measured by aortic pulse wave velocity, PWV) is unclear and there is no existing systematic review.

Objectives
To conduct a systematic review examining whether PR results in alteration of CV risk in COPD (as measured by aPWV).

Methods

An electronic systematic search concordant with PRISMA guidelines was conducted. The search was complete to the 27th of May 2017. Six databases were examined: Embase, Medline, AMED, Web of Science, Cochrane clinical trials, and CINAHL.

Results

This study generated 767 initial matches, which were filtered using inclusion/exclusion criteria. Three studies (201 COPD participants) were included. Our analysis does not confirm that PR affects aPWV but studies were heterogeneous.

Conclusion

There is currently insufficient information on the effect of PR on reducing CV risk in COPD. Therefore controversy remains, with the possibility that there might be some subjects who benefit and others who might experience an increase in CV risk in response to PR. These results will be of value to those interested in gaining a better understanding of the benefits of PR on CV risk in COPD. 

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https://copdrp.biomedcentral.com/articles/10.1186/s40749-017-0026-9

Adherence to COPD treatment: Myth and reality (article from 2017 Respiratory Medicine)

Great Respiratory article from our Italian Friends!!! 

Highlights 

• The level of medication adherence in COPD patients is very low

• Approaches to assess adherence of COPD are burdened with important limitations. 

• Patient views on therapy effectiveness are powerful predictors of reported adherence. 

• The physician can affect adherence in COPD with his/her prescription. 

• In COPD, adherence to inhalation medication is device-related.

COPD is a chronic disease in which effective management requires long-term adherence to pharmacotherapies but the level of adhesion to the prescribed medications is very low and this has a negative influence on outcomes. There are several approaches to detect non-adherence, such as pharmacy refill methods, electronic monitoring, and self-report measures, but they are all burdened with important limitations. Medication adherence in COPD is multifactorial and is affected by patients (health beliefs, cognitive abilities, self-efficacy, comorbidities, psychological profile, conscientiousness), physicians (method of administration, dosing regimen, polypharmacy, side effects), and society (patient-prescriber relationship, social support, access to medication, device training, follow-up). Patient-health care professional communication, especially that between patient and physician or pharmacist, is central to optimizing patient adherence. However, the most realistic approach is to keep in mind that non-adherence is always possible, indeed, probable.

Article is HERE!!! 

Ashtma-Chronic obstructive pulmonary disease overlap syndrome (ACOS): current evidence and future research directions (Free Full text from 2017 COPD Research and Practice)

Chronic obstructive pulmonary disease and asthma are the most frequent chronic respiratory diseases that affect the general population. For a long period of time these two conditions were considered to be separate diseases. However, it became evident that some patients share symptoms and clinical findings from both diseases. 

These patients are considered to represent a distinct phenotype, called asthma-COPD overlap syndrome (ACOS). However, since approximately the one third of the asthmatics smoke the ACOS may primarily define those patients. This is a relatively newly defined clinical syndrome whose underlying mechanisms and most appropriate management remain to be confirmed. In this review, we summarize current knowledge on this syndrome, aiming to update clinicians and help their daily practice.

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https://copdrp.biomedcentral.com/articles/10.1186/s40749-017-0025-x

GOLD 2017 recommendations for COPD patients: toward a more personalized approach (Free full text from COPD Research and Practice)

The Global Initiative for Chronic Obstructive Lung Disease (GOLD), an international committee of experts, has recently published its updated report on diagnosis and management of Chronic Obstructive Pulmonary Disease (COPD). Compared to the previous version, this documents has been an extensively revised: the definition has been simplified, highlighting the importance of respiratory symptoms, and disease development is further discussed, including new insights on lung development. Spirometry is still required for the diagnosis, and it is described as fundamental tool for evaluating prognosis, disease progression, and non-pharmacologic treatment. 

However, differently from the previous version, spirometry is no longer included in the ABCD tool (ie, a practical tool proposed to assess COPD symptom burden and guide pharmacologic treatment), which is now centered exclusively on respiratory symptoms and history of exacerbation. Subsequently, pharmacologic treatment has been shifted towards a more personalized approach, reflecting the ongoing process toward a comprehensive, patient-tailored management.

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https://copdrp.biomedcentral.com/articles/10.1186/s40749-017-0024-y

ERS Guidelines 2017: exhaled biomarkers in lung disease

Breath tests cover the fraction of nitric oxide in expired gas (F_eNO), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for F_eNO, official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and F_eNO, new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management.

Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members.

Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised.

Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice.

Full text:

http://erj.ersjournals.com/content/49/4/1600965

Triple therapy versus LAMA therapy for COPD - TRINITY study (Lancet 2017 article)

Background

Limited data are available for the efficacy of triple therapy with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We compared treatment with extrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; fixed triple) with tiotropium, and BDP/FF plus tiotropium (open triple).

Methods

For this double-blind, parallel-group, randomised, controlled trial, eligible patients had COPD, post-bronchodilator forced expiratory volume in 1 s (FEV₁) of less than 50%, at least one moderate-to-severe COPD exacerbation in the previous 12 months, and a COPD Assessment Test total score of at least 10. After a 2-week run-in period receiving one inhalation per day via single-dose dry-powder inhaler of open-label 18 μg tiotropium, patients were randomised (2:2:1) using a interactive response technology system to 52 weeks treatment with tiotropium, fixed triple, or open triple. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was moderate-to-severe COPD exacerbation rate. The key secondary endpoint was change from baseline in pre-dose FEV₁ at week 52. The trial is registered with ClinicalTrials.gov, number NCT01911364.

Findings

Between Jan 21, 2014, and March 18, 2016, 2691 patients received fixed triple (n=1078), tiotropium (n=1075), or open triple (n=538). Moderate-to-severe exacerbation rates were 0.46 (95% CI 0.41–0.51) for fixed triple, 0.57 (0.52–0.63) for tiotropium, and 0·45 (0.39–0.52) for open triple; fixed triple was superior to tiotropium (rate ratio 0.80 [95% CI 0.69–0.92]; p=0.0025). For week 52 pre-dose FEV₁, fixed triple was superior to tiotropium (mean difference 0·061 L [0.037 to 0.086]; p<0·0001) and non-inferior to open triple (−0.003L [–0.033 to 0.027]; p=0.85). Adverse events were reported by 594 (55%) patients with fixed triple, 622 (58%) with tiotropium, and 309 (58%) with open triple.

Interpretation

In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV₁ of less than 50%, and a history of exacerbations.
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HERE

News alert: According to the last Pharma R&D 2017 Review, Respiratory Drugs the only group decreasing

Pharma R&D 2017 Review, presented recently new drugs by Therapy Groups. Cancer at the top increasing 20%, Respiratory Drugs the only group decreasing.
It is a huge paradox, in the time when we have the progressive increasing of prevalence and mortality of chronic respiratory diseases!!!

Respiratory diseases are STILL among the leading causes of death worldwide.  

Lung infections (mostly pneumonia and tuberculosis), lung cancer and chronic obstructive pulmonary disease (COPD) together accounted for 9.5 million deaths worldwide during 2008, one-sixth of the global total. The World Health Organization estimates that the same four diseases accounted for one-tenth of the disability-adjusted life-years (DALYs) lost worldwide in 2008.

The Global Burden of Disease (GBD) Study recently compared the contribution of major diseases to deaths and disability worldwide for 1990 and 2010. Among the leading causes of death, lower respiratory infections were ranked 3rd in 1990 and 4th in 2010, whereas COPD was ranked 4th in 1990 and 3rd in 2010. Lung cancer rose from 8th- to 5th- commonest cause of death, while tuberculosis fell from 6th to 10th position in the ranking.

The GBD Study also presented rankings for years lived with disability, among which asthma ranked 13th worldwide in 1990 and 14th in 2010, while COPD ranked 6th in 1990 and 5th in 2010. When premature deaths and disability were combined as DALYs  lost, lower respiratory infections were ranked the leading cause worldwide in 1990, and the 2nd most important cause of DALYs lost in 2010. Also among the 25 most important causes were COPD (ranked 6th in 1990 and 9th in 2010), tuberculosis (ranked 8th in 1990 and 13th in 2010) and lung cancer (ranked 24th in 1990 and 22nd in 2010).

Management of COPD in Patients with Cardiovascular Diseases (Hot Topic Review from Drugs 2017)

Dear Friends we are happy to present you Review from Drugs Journal on Hot Topic: Management of COPD in Patients with Cardiovascular Diseases by great Italian Respiratory team: Mario Cazzola, Luigino Calzetta, Barbara Rinaldi, Clive Page, Giuseppe Rosano, Paola Rogliani, Maria Gabriella Matera!!!

Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases often coexist. The mechanistic links between these two diseases are complex, multifactorial and not entirely understood, but they can influence the therapeutic approach. Therapy can be primarily directed towards treating the respiratory symptoms and reducing lung inflammation. Smoking cessation, bronchodilators and inhaled corticosteroids are central to this therapeutic approach. 

The underlying pathophysiological mechanisms that are responsible for the increased cardiovascular risk in COPD remain unclear, but might include arterial stiffness, inflammation and endothelial dysfunction as a consequence of systemic exposure to chemicals in cigarette smoke or airborne pollution. Therefore, it is plausible that treatment of cardiovascular co-morbidities might reduce morbidity and mortality in patients with COPD and, consequently, therapy of COPD should be shifted to the treatment of cardiovascular diseases and systemic inflammation. In support of this approach, early data suggest that patients with COPD treated with angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, statins, anti-platelet drugs or β-adrenoceptor blockers may have improved survival and reduced hospitalisation from acute exacerbations of COPD. In this review, the potential impact of traditional therapies for COPD that are centred on treating the lungs and newer strategies potentially able to affect and mitigate cardiovascular risks in patients with COPD are discussed.

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Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline 2017 (Free full text)

This document provides clinical recommendations for treatment of chronic obstructive pulmonary disease (COPD) exacerbations.

Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the Task Force's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of COPD experts.

After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made: 1) a strong recommendation for noninvasive mechanical ventilation of patients with acute or acute-on-chronic respiratory failure; 2) conditional recommendations for oral corticosteroids in outpatients, oral rather than intravenous corticosteroids in hospitalised patients, antibiotic therapy, home-based management, and the initiation of pulmonary rehabilitation within 3 weeks after hospital discharge; and 3) a conditional recommendation against the initiation of pulmonary rehabilitation during hospitalisation.

The Task Force provided recommendations related to corticosteroid therapy, antibiotic therapy, noninvasive mechanical ventilation, home-based management, and early pulmonary rehabilitation in patients having a COPD exacerbation. These recommendations should be reconsidered as new evidence becomes available.

Free full text is 

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The impact of anaemia and iron deficiency in COPD: A clinical overview (free full text from 2017 Revista Portuguesa de Pneumologia)

Anaemia is increasingly recognised as an important comorbidity in the context of chronic obstructive pulmonary disease (COPD), but remains undervalued in clinical practice. This review aims to characterise the impact of anaemia and iron deficiency in COPD.

Methods

Literature review of studies exploring the relationship between anaemia/iron deficiency and COPD, based on targeted MEDLINE and Google Scholar queries.

Results

The reported prevalence of anaemia in COPD patients, ranging from 4.9% to 38.0%, has been highly variable, due to different characteristics of study populations and lack of a consensus on the definition of anaemia. Inflammatory processes seem to play an important role in the development of anaemia, but other causes (including nutritional deficiencies) should not be excluded from consideration. Anaemia in COPD has been associated with increased morbidity, mortality, and overall reduced quality of life. The impact of iron deficiency, irrespective of anaemia, is not as well studied, but it might have important implications, since it impacts production of red blood cells and respiratory enzymes. Treatment of anaemia/iron deficiency in COPD remains poorly studied, but it appears reasonable to assume that COPD patients should at least receive the same type of treatment as other patients.

Conclusions

Anaemia and iron deficiency continue to be undervalued in most COPD clinical settings, despite affecting up to one-third of patients and having negative impact on prognosis. Special efforts should be made to improve clinical management of anaemia and iron deficiency in COPD patients as a means of achieving better patient care.

Free full text:

http://www.sciencedirect.com/science/article/pii/S2173511517300052

Chronic obstructive pulmonary disease and diabetes (free full text from COPD Research and Practice)

Diabetes occurs more often in individuals with COPD than in the general population, however there are still many issues that need to be clarified about this association. The exact prevalence of the association between diabetes and COPD varies between studies reported, however it is known that diabetes affects 2–37 % of patients with COPD, underlining the need to better understand the link between these two conditions. In this review, we evaluated the epidemiological aspects of the association between diabetes and COPD analyzing potential common issues in the pathological mechanisms underlying the single disease. 

The close association suggests the occurrence of similar pathophysiological process that leads to the development of overt disease in the presence of conditions such as systemic inflammation, oxidative stress, hypoxemia or hyperglycemia. Another, but not less important, aspect to consider is that related to the influence of the pharmacological treatment used both for the patient affected by COPD and from that affected by diabetes. It is necessary to understand whether the treatment of COPD affect the clinical course of diabetes, it is also essential to learn whether treatment for diabetes can alter the natural history of COPD.

Free full text:

https://copdrp.biomedcentral.com/articles/10.1186/s40749-015-0005-y

LAMA plus LABA versus LABA plus ICS for stable COPD (free full text from The Cochrane Library)

BACKGROUND:

Three classes of inhaler medications are used to manage chronic obstructive pulmonary disease (COPD): long-acting beta-agonists (LABA), long-acting muscarinic antagonists (LAMA), and inhaled corticosteroids (ICS). When two classes of medications are required, LAMA plus LABA (LAMA+LABA) and LABA plus ICS (LABA+ICS) are often selected because these combinations can be administered via a single medication device. The previous Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidance recommended LABA+ICS as the first-line treatment for managing stable COPD in high-risk people of categories C and D. However, the updated GOLD 2017 guidance recommends LAMA+LABA over LABA+ICS.

 OBJECTIVES:

To compare the benefits and harms of LAMA+LABA versus LABA+ICS for treatment of people with stable COPD.

SEARCH METHODS:

We performed an electronic search of the Cochrane Airways Group Specialised Register (2 February 2016), ClinicalTrials.gov (4 June 2016), and the World Health Organization Clinical Trials Search Portal (4 June 2016), followed by a handsearch (5 June 2016). Two review authors screened and scrutinised the selected articles.

SELECTION CRITERIA:

We included individual randomised controlled trials, parallel-group trials, and cross-over trials comparing LAMA+LABA and LABA+ICS for stable COPD. The minimum accepted trial duration was one month and trials should have been conducted in an outpatient setting.

DATA COLLECTION AND ANALYSIS:

Two review authors independently extracted data and evaluated risk of bias. We resolved any discrepancies through discussion. We analysed dichotomous data as odds ratios (OR), and continuous data as mean differences (MD), with 95% confidence interval (CI) using Review Manager 5. Exacerbations were measured by counting the number of people experiencing one or more exacerbation.

MAIN RESULTS:

We included 11 studies comprising 9839 participants in our quantitative analysis. Most studies included people with moderate to severe COPD, without recent exacerbations. One pharmaceutical sponsored trial that included only people with recent exacerbations was the largest study and accounted for 37% of participants. All but one study were sponsored by pharmaceutical companies, thus we rated them as having a high risk of 'other bias'. The unsponsored study was at high risk of performance and detection bias, and possible selective reporting.Five studies recruited GOLD Category B participants, one study recruited Category D participants, two studies recruited Category A/B participants, and three studies recruited participants regardless of category. Follow-up ranged from 6 to 52 weeks.Compared to the LABA+ICS arm, the results for the pooled primary outcomes for the LAMA+LABA arm were as follows: exacerbations, OR 0.82 (95% CI 0.70 to 0.96, P = 0.01, I² = 17%, low quality evidence); serious adverse events (SAE), OR 0.91 (95% CI 0.79 to 1.05, P = 0.18, I² = 0, moderate quality evidence); St. George's Respiratory Questionnaire (SGRQ) total score change from the baseline, MD -1.22 (95% CI -2.52 to 0.07, P = 0.06, I² = 71%, low quality evidence); and trough forced expiratory volume in one second (FEV₁) change from the baseline, MD 0.08 L (95% CI 0.06 to 0.09, P < 0.0001, I² = 50%, moderate quality evidence). Compared to the LABA+ICS arm, the results for the pooled secondary outcomes for the LAMA+LABA arm were as follows: pneumonia, OR 0.57 (95% CI 0.42 to 0.79, P = 0.0006, I² = 0%, low quality evidence); all-cause death, OR 1.01 (95% CI 0.61 to 1.67, P = 0.88, I² = 0%, low quality evidence); and SGRQ total score change from the baseline of 4 points or greater (the minimal clinically important difference for the SGRQ is 4 points), OR 1.25 (95% CI 1.09 to 1.44, P = 0.002, I² = 0%, moderate quality evidence).

AUTHORS' CONCLUSIONS:

For the treatment of COPD, LAMA+LABA has fewer exacerbations, a larger improvement of FEV₁, a lower risk of pneumonia, and more frequent improvement in quality of life as measured by an increase over 4 units or more of the SGRQ. These data were supported by low or moderate quality evidence generated from mainly participants with moderate to severe COPD in heterogeneous trials with an observation period of less than one year. Our findings support the recently updated GOLD guidance.
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http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD012066.pub2/abstract;jsessionid=41D11BDBD96F61F
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