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Chronic obstructive pulmonary disease (COPD) is a heterogeneous multisystem disease characterised by irreversible airflow limitation. The varied nature of clinical presentation has led to a variety of definitions and descriptors over the years and indeed centuries. Increasingly, phenotypic clusters or treatable traits are being recognised, which allows the sub-classification of the generic COPD cohort into groups that have common features and specific treatment responses. The concept of personalised medicine is emerging in COPD as in other diseases. A lot of this new understanding has come from large multicentre and often industry-supported trials. The beginning of the century marked a particular focus on COPD and its treatment. Initial study results were modest, however, large-scale investigations continue to be published that better our understanding of the disease, and more importantly, its treatment.
While the opening decades of the 21st century are an exciting time to be working in the area of COPD, management decisions are becoming more complex. There are a large and confusing number of inhaled and oral therapies for COPD and a large number of trials to support the use of each of them. In this article, we aim to review the current COPD guidelines and summarise some of the major COPD trials that support this guidance.
Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 2018
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) is an expert group that was established in 1997 as a collaboration involving the World Health Organisation (WHO), the American National Institutes of Health (NIH) and the American National Heart, Lung, and Blood Institute (NHLBI). Their aim was to distil current evidence into a usable and authoritative clinical guideline. The GOLD group is considered impartial and both their expert panels and readership are international. The current rate of publication in the COPD literature means that they have remained very active over the last 17 years. GOLD released its first report in 2001 as a means to aid physicians in the diagnosis and management of COPD by providing a summary of best validated concepts of COPD pathogenesis at that time along with available evidence on the most appropriate management and prevention strategies. Since then, the report has been updated on a regular basis, the latest being the 2018 report, which we review in this article.
Diagnosis of COPD requires a combination of symptoms, exposure, history and spirometry. Symptoms include dyspnoea and chronic cough or sputum production, while exposure to risk factors is principally, but not exclusively, smoking.
Indoor exposure to biomass smoke and slate mining are two examples of other exposure risks. Spirometry is vital in diagnosing COPD objectively. An FEV1/FVC ratio of <0.7 post bronchodilator confirms the presence of fixed airway obstruction.
Categorising patients into risk groups; A, B, C and D has been recommended in the last few reports (Figure 1). Patients can be categorised into these categories according to their spirometry (GOLD stages I to IV), modified British Medical Council (mMRC) breathless score, COPD Assessment Test (CAT) score and frequency of exacerbation. The purpose of this is to aid treatment choice.
Over the years the preference has shifted from inhaled corticosteroids (ICS) to long-acting β2-agonists (LABA) or long-acting muscarinic antagonists (LAMA) in the early treatment of COPD. The present guidelines recommend that group A patients should be started off with a single bronchodilator, whereas in group B a single long-acting bronchodilator (LABA or LAMA) can be initially trialled and possibly stepping up to a LABA-LAMA combination should symptoms persist.
In group C patients, LAMA is preferred as the starting treatment, with a preference to stepping up to a LAMA-LABA combination rather than a LAMA-ICS combination, should there be further exacerbations.
In group D patients, LABA-LAMA should be the initial treatment and possibly increasing to triple therapy (LAMA-LABA-ICS) in frequent exacerbators.
The final step is an addition of a macrolide or a phosphodiesterase-4 inhibitor. Consideration should also be given regarding withdrawing ICS in group D, as some clinical trials have shown lack of efficacy and elevated risk of side effects with ICS. Smoking cessation and vaccination should be advised across all groups.
Clinical trials – inhaled therapy
The ISOLDE trial was published in the BMJ in the year 2000. It was one of the first major trials that studied the effects of long-term corticosteroids in patients with moderate to severe COPD. This three-year trial unexpectedly showed no difference in the rate of decline of FEV1 for treatment group versus placebo, however, the authors reported fewer exacerbations and slower decline in health status in the treatment group. Hence this trial supported the use of ICS in this group of COPD patients.
The TRISTAN trial in 2003 also looked at the role of ICS in COPD. The authors studied the effects of combination therapy (ICS-LABA) versus ICS or LABA alone. This study concluded that combination therapy produces better control of symptoms and lung function, with no greater risk of side effects than that with use of either component alone.
The three-year TORCH trial was published in the New England Journal of Medicine (NEJM) in 2007 and provided initial evidence of adverse effects from ICS. The authors reported an increased rate of pneumonia in treatment groups receiving ICS (fluticasone propionate). However, there was no significant difference in mortality rate across all study groups. These findings were confirmed by the FLAME trial in 2016 that compared indacaterol-glycopyrronium versus salmeterol-fluticasone and also found an increased rate of pneumonia in the ICS group. The authors also reported a reduced rate of exacerbations in the LABA-LAMA group.
UPLIFT in 2008 was the first trial to provide insight into the long-term effects of a LAMA alone in COPD patients. This four-year trial demonstrated an improvement in lung function, quality-of-life and exacerbation rates in patients on tiotropium versus placebo.
The INSPIRE trial also published in 2008 looked at ICS-LABA combination versus LAMA alone. There was no difference in exacerbations between the two groups, but interestingly mortality and quality-of-life was better in the salmeterol-fluticasone group. Pneumonia rates were higher in the ICS groups, which was consistent with the TORCH trial.
In the POET-COPD trial in 2011 the effect of LAMA was directly compared to LABA. This one-year randomised, double-blind, double-dummy trial studied patients with moderate to very severe COPD on tiotropium or salmeterol.
Patients on tiotropium were found to have reduced rates of exacerbation. In addition, the rate of exacerbation in the LAMA group who were already receiving ICS at baseline, but was discontinued during the study period, was no different from those who continued to receive ICS during the study. This finding was consistent with the COSMIC 2005 study that demonstrated withdrawal of ICS did not increase the rate of moderate or severe exacerbations. The authors of COSMIC, however, reported an increase in mild exacerbations and sustained decreased in lung function and dyspnoea score following ICS withdrawal.
The SPARK trial, 2013 compared combination treatment of LABA-LAMA versus the individual agents alone. This one-year study concluded that combination therapy was superior in preventing moderate to severe exacerbations compared to a single agent.
The SALFORD lung study was published in 2016. This utilised a pragmatic randomised design and attempted to minimise exclusion criteria and therefore provide information on more ‘real world’ patients rather than the highly selected and possibly unrepresentative cohorts of earlier large studies. The effectiveness of once-daily dosing regimen using a once-daily combination of ICS-LABA (fluticasone furoate-vilanterol) was compared to usual care. It was found that patients with COPD and a history of exacerbations had lower rates of exacerbations being on a once-daily treatment regimen than usual care. There was no significant difference in serious adverse events between both groups.
Triple therapy has been studied more extensively in the recent years starting off with the CLIMB trial in 2009. This three-month study reported the addition of combination ICS-LABA to LAMA reduced exacerbation rates and improved morning symptoms.
The WISDOM trial in 2014 reported that stable COPD patients on triple therapy were safely withdrawn from ICS without any increased rates of exacerbations. There was also no reported increase in cases of pneumonia between groups as previously reported in the TORCH and INSPIRE trials.
The most recent trial for triple therapy is the IMPACT trial published in the NEJM in May 2018. This study compared once-daily triple therapy to once-daily dual therapy (ICS-LABA or LAMA-LABA). It was concluded from this study that patients had lower rates of moderate and severe exacerbations on the triple therapy. Triple therapy also resulted in a lower rate of hospitalisation due to COPD. This study also supports existing evidence pertaining to increased risk of pneumonia with ICS, as authors also reported a higher pneumonia rate in the ICS groups.
Clinical trials – oral therapy
Albert et al reported on a major trial in 2011 to determine the effectiveness of azithromycin in reducing exacerbation rates in COPD. Prior to that, there had been a few small trials with mixed results. This one-year follow-up trial suggested that subjects that had taken azithromycin daily for a year on top of their usual treatment had decreased frequency of exacerbations and improved quality-of-life. A small percentage of subjects, however, had hearing decrements possibly secondary to azithromycin (placebo group, 20 per cent versus treatment group, 25 per cent).
The findings of this study were supported by another clinical trial, COLUMBUS 2014. This three-year follow-up study showed maintenance therapy with azithromycin 500mg three times a week for a year was superior in decreasing exacerbations rates compared to placebo. The most common adverse event in the study group was diarrhoea (treatment group, 19 per cent versus placebo group, 2 per cent).
The efficacy and safety of roflumilast, a phosphodiesterase-4 inhibitor was first studied in COPD patients in 2005. Study subjects were assigned to a once-daily dose of roflumilast (250mcg or 500mcg) or placebo for 24 weeks. Post-bronchodilator FEV1 was better in the treatment group at the end of the treatment phase. Calverly et al studied an extended treatment duration of roflumilast of one year. In stable COPD patients, roflumilast produced a modest, but significant improvement in lung function without changing exacerbation rate or health status.
More recently, the RE2POND trial in 2016 had rather disappointing results, where it failed to show a statistically significant reduction in moderate to severe exacerbations with roflumilast.
While recognised for many centuries, COPD remains a challenging condition to diagnose and manage effectively. Future clinical trials will likely produce new treatment regimens that will add to an already vast variety of treatment options.
COPD phenotyping may also provide a whole new perspective and new management options for COPD. Despite the rapid pace of change the fundamentals of accurate diagnosis, staging, risk avoidance and exercise prescription remain the cornerstones of care for the patient with COPD.