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Current controversies in the pharmacological treatment of COPD

Dave Singh (1), Nicolas Roche (2), David Halpin (3), Alvar Agusti (4), Jadwiga Wedzicha (5), Fernando Martinez (6)

(1) Centre for Respiratory Medicine and Allergy, Medicines Evaluation Unit, University

of Manchester & University Hospital of South Manchester, Manchester, United

Kingdom, M23 9LT

(2) Cochin Hospital Group, Assistance Publique Hôpitaux de Paris, University Paris

Descartes (EA2511), Paris, France

(3) University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, UK

(4) Thorax Institute, Hospital Clinic, IDIBAPS, University of Barcelona, CIBERES,

Spain

(5) Airways Disease Section, National Heart and Lung Institute, Imperial College

London, London, United Kingdom

(6) Weill Cornell Medical College, New York, New York, USA; University of Michigan

Health System, Ann Arbor, MI, USA

Corresponding author

Dave Singh

Centre for Respiratory Medicine and Allergy, Medicines Evaluation Unit, University of

Manchester & University Hospital of South Manchester, Manchester, United Kingdom, M23

9LT

dsingh@meu.org.uk

Tel: +44 1619464073

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Abstract

Clinical phenotyping is currently used to guide pharmacological treatment decisions in

COPD, a personalized approach to care. Precision medicine integrates biological (endotype)

and clinical (phenotype) information for a more individualised approach to pharmacotherapy,

in order to maximise the benefit versus risk ratio. Biomarkers can be used to identify

endotypes. To evolve towards precision medicine in COPD, the most appropriate biomarkers

and clinical characteristics that reliably predict treatment responses need to be identified.

Forced expiratory volume in 1 second (FEV1) is a marker of COPD severity, and has

historically been used to guide pharmacotherapy choices. However, we now understand that

the trajectory of FEV1 change, as an indicator of disease activity, is more important than a

single FEV1 measurement. There is a need to develop biomarkers of disease activity to

enable a more targeted and individualised approach to pharmacotherapy.

Recent clinical trials testing commonly used COPD treatments have provided new

information that is likely to influence pharmacological treatment decisions both at initial

presentation and at follow up. In this Perspective, we consider the impact of recent clinical

trials on current COPD treatment recommendations. We also focus on the movement towards

precision medicine, and propose how this field needs to evolve in terms of using clinical

characteristics and biomarkers to identify the most appropriate patients for a given

pharmacological treatment.

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Introduction

COPD is a complex condition, encompassing many elements that contribute to its clinical

presentation. COPD is also heterogeneous, as these different elements vary in both presence

and severity between patients(1). These characteristics may be dynamic, varying over time

within the same patient(2). The variability between COPD patients means that an

individualised approach is required for pharmacological treatment (2, 3).

Clinical phenotypes are subgroups of patients defined by clinical characteristics and sharing

common clinical outcomes (e.g., exacerbations, response to treatment)(4). In 2011, the

Global initiative for the treatment of Obstructive Lung Disease (GOLD) proposed a

combined assessment of forced expiratory volume in 1 second (FEV1), symptoms and

exacerbation history, resulting in four groups representing clinical phenotypes (A/B/C/D)(5).

Pharmacological treatments were proposed for each phenotype, targeting the short- and long-

term relief of symptoms and the long term risk reduction of future events such as

exacerbations (or death). Potential criticisms of this approach are that these clinical

phenotypes require prospective validation regarding their links with future outcomes and

treatment responses, and that some pharmacological treatment propositions were not

supported by firm clinical evidence(3). Nevertheless, many national respiratory societies have

embraced the GOLD principles to construct COPD guidelines, although with several

variations(6).

Each clinical feature of COPD is likely caused by more than one biological mechanism.

Consequently, pharmacological targeting of clinical characteristics does not specifically

match the drug to underlying biological mechanisms, and may result in limited efficacy. An

endotype is a subtype of a (clinical) condition defined by a distinct pathophysiological

mechanism(3). An endotype gives rise to one or more clinical characteristics, and clinical

phenotypes can be the result of multiple endotypes. The “precision medicine” strategy uses

both biological (endotype) and clinical (phenotype) information to identify the most

appropriate individuals for a given pharmacological treatment, in order to maximise the

benefit versus risk ratio(7). COPD pharmacotherapy faces a challenge to incorporate

precision medicine, as easily accessible biomarkers that identify clinically relevant endotypes

need to be developed.

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Recent studies have raised issues about the clinical characteristics and biomarkers that can

reliably predict treatment responses, and whether the existing evidence supports current

pharmacological treatment recommendations. This article focuses on current controversies in

COPD pharmacological management, and considers the future evolution of COPD

pharmacotherapy towards precision medicine.

Is FEV1 useful for guiding treatment decisions?

At a population level, there is a loose association in COPD cross-sectional studies between

FEV1 and symptoms; consequently, FEV1 poorly predicts the symptom burden on an

individual level (1) and is a suboptimal measurement to guide symptom based treatment

decisions. However, the change in FEV1 in COPD randomised clinical trials (RCTs) is still a

useful measurement, as improvements in FEV1 associate with improvements in symptoms,

health status and exacerbation rates(8, 9).

Inhaled corticosteroid/long acting beta-agonist (ICS/LABA) combinations reduce

exacerbation rates, and improve lung function and health status (10-13). RCTs of ICS/LABA

combinations commonly enrich the population to include individuals more likely to

exacerbate, in order to maximize treatment efficacy(13-15). The ECLIPSE and COPDgene

longitudinal cohort studies demonstrated that the past exacerbation history is a better

predictor of future exacerbations than FEV1 (16, 17). Furthermore, a notable proportion

(22%) of patients with FEV1 50 – 80% predicted in ECLIPSE had ≥2 exacerbations (defined

as frequent exacerbators) each year for 3 years(16). Therefore, relying on FEV1 to identify

patients at risk of exacerbations (e.g. using 50% predicted as a threshold) may prevent some

patients from receiving appropriate pharmacotherapy. Indeed, recent evidence shows that

ICS/LABA reduce exacerbations in patients with an exacerbation history and FEV1 up to

70% predicted (14).

Long acting bronchodilators improve lung function, thereby improving symptoms and

exercise performance, and prevent exacerbations(11, 18, 19). These agents show similar

efficacy in moderate (GOLD II) compared to more severe (GOLD III / IV) COPD

patients(20, 21), indicating that FEV1 does not predict bronchodilator treatment response.

Furthermore, short acting bronchodilator reversibility does not predict response to long acting

bronchodilators or ICS/LABA combinations(22, 23), as bronchodilator reversibility can

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change between visits(24) and patients with a negative reversibility test can still obtain

clinical benefit from a long acting bronchodilator.

An “FEV1-free” approach to pharmacotherapy in COPD has been proposed(25), where the

use of long-acting bronchodilators would be directed by symptoms and the presence of

exacerbations. The use of anti-inflammatory treatments would be recommended if the patient

continues to suffer exacerbations despite appropriate bronchodilator treatment; see Figure 1.

The GOLD C and D categories comprise 3 different patient subgroups; low FEV1 alone,

exacerbation history alone or both. This causes confusion in clinical practice regarding

pharmacological treatments. The “FEV1-free” approach makes the definition of GOLD C and

D more homogeneous, including only frequent exacerbators. The “FEV1-free” approach

applies to pharmacotherapy only, as spirometry is required for COPD diagnosis, and FEV1

remains a prognostic risk marker for mortality(26) and is required when considering

interventional care for COPD (i.e., lung volume reduction or lung transplantation).

Targeting treatment towards disease activity

The different components of COPD can be categorized into severity, activity and impact

groupings(27). Severity refers to functional impairment, including airflow limitation,

hyperinflation, arterial hypoxemia and reduced exercise capacity(28). Disease activity refers

to features associated with disease progression, such as exacerbations, FEV1 decline and

weight loss(27). Impact refers to the individual patient`s perception of disease severity and

activity(27). Bronchodilators improve severity (lung function) which consequently reduces

the impact level. However, as already discussed, the level of impact rather than severity

should guide individual treatment decisions regarding bronchodilator use; this is illustrated in

Figure 2, which also shows that pharmacological treatments can target disease activity, such

as preventing exacerbations. RCTs have used inclusion criteria to select individuals with

more active disease based on exacerbation history(13, 14, 29, 30). We now consider

alternative means of assessing disease activity, through longitudinal assessments and

biomarkers.

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Longitudinal data

The speed of lung function loss with age is the paradigmatic marker of disease activity.

However, years of follow up are needed to be confident of the rate of change. FEV1 does not

decline precipitously in all treated COPD patients, remaining stable or even improving in a

significant proportion(31). Furthermore, a recent analysis of 3 independent cohorts showed

that COPD can be the result of different trajectories of lung function decline, depending on

underlying mechanisms including failure to reach maximal lung growth (32). The mean rate

of lung function decline was 27 mls / year compared to 53mls / year in individuals with low

and normal FEV1 in early adult life respectively, suggesting greater disease activity in the

latter group. A single FEV1 measurement is a severity marker, but may be misleading

regarding disease activity.

COPD RCTs have not proved, as a primary endpoint, that pharmacotherapy reduces the rate

of lung function decline. However, post-hoc analysis of a 3 year RCT showed a reduced rate

of FEV1 decline with ICS/LABA treatment and the monocomponents(33), while a pre-

specified subgroup analysis showed similar results for LAMA treatment in GOLD II

patients(20). The SUMMIT study showed that ICS / LABA, but not LABA monotherapy,

reduced the rate of FEV1 decline in COPD patients with FEV1 50 – 70% predicted, but a

definitive conclusion from this secondary outcome could not be made as the primary outcome

(mortality) was negative, and a hierarchical testing approach was used(34). These studies

have shown attenuation of FEV1 decline by pharmacotherapies ranging from 6 – 16 mls /

year. These effect sizes may be greater in patient subgroups with more rapid FEV1 decline;

risk factors for rapid decline include current smoking, exacerbations and emphysema(16, 35).

Smoking cessation reduces the rate of lung function decline(36), and the evidence reviewed

here suggests an effect of long acting bronchodilators and ICS through exacerbation

prevention, thereby reducing disease activity. There is a need for RCTs that specifically

address pharmacological approaches to prevent emphysema progression.

Biomarkers

Fibrinogen is a biomarker of cardiovascular risk, and predicts exacerbation risk and mortality

in COPD patients(37). Plasma fibrinogen measurements have been accepted by the U.S. Food

and Drug Administration as a biomarker for enriching RCTs with patients more likely to

suffer with these outcomes, when used in conjunction with clinical information such as the

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past history of exacerbations. Importantly, fibrinogen cannot yet be used at an individual

level in clinical practice; it is a biomarker that can be used at a group level to identify patients

with greater disease activity. There are currently no disease activity biomarkers validated for

use at an individual level.

Biomarkers that have been investigated include club cell protein 16 (CC-16) and soluble,

circulating form of the receptor for advanced glycation end products (sRAGE). CC16 is a

protective immunosuppressant secreted by Clara cells; low CC16 levels are associated with

lung function decline(38, 39). sRAGE may be associated with emphysema severity and

progression(40). Most of the evidence for these biomarkers comes from cohort studies, or

small clinical trials. Their potential usefulness to enrich the population studied, and / or to

measure treatment effects, should be prospectively evaluated in large RCTs. The validation

and harmonisation of the laboratory measurement methods also needs to be established.

A panel of several biomarkers may provide more reliable information than a single one; for

example, patients with persistent systemic inflammation assessed by blood leukocytes and

serum IL-6, CRP and fibrinogen had significantly higher all-cause mortality (13% vs. 2%)

and exacerbation frequency (1.5 vs. 0.9/year)(41). Additionally, a biomarker panel increased

the ability of clinical variables to predict future exacerbations and mortality (42, 43).

Biomarkers of disease activity are likely to be most useful when used with clinical

measurements.

Combining long acting bronchodilators; what is the benefit versus monotherapy?

Combination inhalers containing a LABA + LAMA cause improvements in FEV1 compared

to placebo that are usually approximately 250 – 300 mls at peak and 150 – 200 mls at

trough(44-46). These combination inhaler effects on FEV1 are greater than long acting

bronchodilator monotherapies, with treatment differences of approximately 150 mls at peak

and 50 – 90 mls at trough(44-46). The important clinical question is the degree of symptom

improvement associated with these lung function changes. Initial studies used lung function

as a primary endpoint for regulatory purposes, and were not specifically powered or designed

for patient reported outcome (PRO) measurements(45-47). These studies showed that the

mean PRO improvements with LABA/LAMA combinations versus placebo exceeded the

minimal clinically important difference (MCID) thresholds for breathlessness scores (>1

point change in the transition dyspnoea intensity (TDI) focal score) and health related quality

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of life (>4 point reduction in the St Georges Respiratory Questionnaire (SGRQ) total score)

(48), while monotherapies often failed to meet these MCID thresholds versus placebo.

Individual responder analysis also showed that significantly more patients reached the MCID

thresholds with dual therapy versus monotherapy. However, the mean differences between

dual bronchodilators versus monotherapy were often small in magnitude or not statistically

significant. Subsequent studies specifically designed with PROs as the primary endpoint(49,

50), and pooled analysis with greater statistical power(51), have shown statistically

significant differences of 0.5 for TDI, and 2 for SGRQ for this treatment comparison. These

are lower than the MCID thresholds, but the associated reductions in reliever medication use

suggest clinical relevance(44, 48).

The daily variation in lung function is reduced with two short acting bronchodilators

compared to one, suggesting greater stabilisation of airway tone(24). LABA/LAMA

combinations may also provide increased airway stabilisation. RCTs usually focus on

improvements in FEV1 and symptoms with bronchodilators, but the prevention of short-term

clinical deterioration, which may progress to exacerbation, is also of importance.

Long acting bronchodilator monotherapies reduce exacerbation rates(11, 19). There is also a

greater effect on exacerbations with LABA/LAMA compared to LAMA monotherapy in

patients at risk of exacerbations; indacaterol /glycopyronium reduced exacerbations requiring

oral corticosteroids and / or antibiotics by 12% compared to glycopyronium(30). There was

also a reduction in mild exacerbations requiring increased bronchodilator treatment, which

may be due to better airway stabilisation with LABA/LAMA treatment.

Exacerbations may be associated with increased airway inflammation(52), but there is no

consistent evidence from clinical trials that bronchodilators have anti-inflammatory effects.

Long acting bronchodilators improve airflow obstruction, air trapping and hyperinflation,

thus reducing dyspnoea and improving exercise performance(18). These improvements in

lung mechanics and clinical status probably allow patients to cope better with the

pathophysiological impact of factors that may trigger exacerbations, such as infections(53).

COPD patients at high risk of cardiovascular events are often excluded from RCTs. The

SUMMIT study in patients at increased risk of cardiovascular disease showed no increase in

adverse cardiac events with LABA treatment(34). More studies in high risk COPD patients,

and real world observational studies, would provide further reassurance about long acting

bronchodilator safety.

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ICS/LABA; benefit versus risk

Many RCTs have shown a reduction in exacerbations of approximately 25-30% for various

ICS/LABA versus LABA, suggesting a “class effect” for ICS(13-15). ICS may have side

effects; RCTs, meta-analyses and observational studies concur in finding an increased rate of

non-fatal pneumonia in patients receiving ICS(11, 13, 14, 54). Risk factors include past

exacerbations, low BMI or low FEV1(55); this may explain the lack of increase in

pneumonia events in the SUMMIT study which enrolled moderate COPD patients without a

requirement for past exacerbations. This effect may relate more to the dose than to the

properties of individual molecules. Observational studies suggest increased risk of

mycobacterial infection(56, 57), diabetes occurrence or aggravation(58), bone fractures(59)

and cataract(60) with ICS, but residual confounders could influence the results. RCT

evidence exists only for skin bruises(61) and loss of bone mineral density(59), indicating that

ICS can cause clinically relevant systemic effects. Other ICS systemic side effects are

difficult to firmly demonstrate in RCTs due to the long duration of follow-up and large

sample size required.

COPD patients with greater sputum eosinophil counts have a better response to corticosteroid

treatment(62, 63). Sputum sampling is only performed in specialist centres. Blood eosinophil

counts are more accessible, and show a degree of correlation to sputum eosinophils(64). Post-

hoc analyses of RCTs investigating ICS/LABA combinations versus LABA monotherapy

have reported greater effects of ICS/LABA on exacerbation prevention in patients with

higher blood eosinophil counts(65-67). Post-hoc analysis of the INSPIRE study reported that

ICS/LABA had a significantly greater effect on exacerbations than LAMA in patients with

blood eosinophils >2% (rate ratio 0.75), but there was no difference with blood eosinophils

<2%(66). Similarly, ICS withdrawal in the WISDOM study increased the exacerbation rate

only in patients with blood eosinophils >2%(68). Although a threshold of 2% has been

commonly used in these analyses, the effects of ICS appear to become greater when using

higher thresholds(65, 67, 68), and it is not clear whether percentage or absolute eosinophil

counts should be used. It has also been reported that blood eosinophils >2% predict a reduced

rate of FEV1 decline with ICS compared to placebo (difference 33.9 mls / year)(69).

Prospective RCTs are needed to validate the use of blood eosinophil counts to predict ICS

response, and to identify the appropriate cut-off level. The mechanism(s) for the differential

effects of ICS according to eosinophil counts remain unclear. Higher blood eosinophil counts

in some (but not all) analyses predict higher exacerbation rates(64, 70), suggesting more

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active disease, with eosinophils ≥340 cells/μl predicting an increased exacerbation risk in

COPD patients in the Copenhagen general population study(70).

Initial pharmacological treatment

GOLD makes propositions for initial pharmacotherapy, with different options for groups A-

D(5). Pharmacotherapy for groups A and B is dominated by short and long acting

bronchodilator treatments. The majority of COPD patients on long acting bronchodilator

monotherapy remain significantly breathless(71). There is no evidence to suggest which

patients should initially receive a LABA/LAMA combination. This could be investigated in

patients who have not received long acting bronchodilator treatments previously, unlike the

majority of patients in published studies. ICS/LABA should not be used for groups A and B,

and RCTs have shown superiority for LABA/LAMA over ICS/LABA in these patients for

lung function and symptoms(72, 73).

Groups C and D include patients with frequent exacerbations defined by a history of ≥2

moderate to severe exacerbations or one hospitalisation in the last year. Clinical outcomes

including future exacerbation risk, health-related quality of life, FEV1 decline and mortality

are significantly impaired in patients with ≥ 2 exacerbations per year(16). Many exacerbation

events are unreported (74, 75), and a threshold of 2 events using patient recall may

underestimate the true event rate. Exacerbation frequency may change(16), and using a lower

threshold (a single exacerbation event in a year) may identify patients with no further events.

GOLD uses one hospitalisation to define a patient at high-risk of future exacerbations,

recognising the importance of event severity which influences the time to recovery(76).

RCTs assessing the effects of drugs on exacerbation rates have historically used one

exacerbation in the previous year as an inclusion criteria(13, 14). Current GOLD propositions

assume that results from these studies predict the effects in patients with ≥2 exacerbations /

year, but this mostly remains untested.

The positioning of LAMA as a first line option for frequent exacerbators is based on robust

evidence demonstrating effects on exacerbations compared to placebo(19, 77). Furthermore,

the INSPIRE study in patients with severe airflow obstruction and a history of exacerbations

showed no difference in exacerbation rate after 2 years treatment with tiotropium compared

to fluticasone propionate / salmeterol(78). Systemic corticosteroid treatment for

exacerbations was less frequent with ICS/LABA treatment, while antibiotic use was less

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frequent with tiotropium. This suggests that initial pharmacotherapy could be tailored to

prevent exacerbation subtypes.

Follow up pharmacological treatment

GOLD does not provide guidance on pharmacological strategies during follow-up, when

treatment may be adjusted according to the initial treatment response; this potentially

includes stopping ineffective therapies. The comparative benefits of adding or switching

therapies if patients remain symptomatic on initial therapy need to be better characterised.

The introduction of dual bronchodilator combinations raises the issue of the comparative

efficacy of LABA / LAMA versus ICS /LABA. Indacaterol/glycopyrronium had a greater

effect on exacerbations than salmeterol/fluticasone propionate in a subgroup of patients with

one exacerbation in the previous year included in an RCT (79). The recently published

FLAME study recruited 3362 patients with ≥ 1 exacerbation in the previous year to compare

these combinations over one year(29). Indacaterol/glycopyrronium showed superiority on the

rate of all exacerbations (11% reduction, p=0.003), with moderate to severe exacerbations

reduced by 17% (p<0.001). There was evidence of significantly better FEV1 (62 mls) and

health status, and lower pneumonia incidence with indacaterol/glycopyrronium. While

INSPIRE showed similarity between LAMA and ICS/LABA for exacerbation reduction(78),

FLAME now demonstrates a superiority for LABA/LAMA in this regard, across different

severities of exacerbation. ICS treatment has been perceived to be an essential part of

exacerbation prevention strategies; FLAME shows an effective alternative strategy without

ICS.

There is little evidence for exacerbation reduction when stepping up from two medications

(either ICS/LABA or LAMA/LABA) to triple therapy(80), although there are benefits for

lung function and patient reported outcomes(81, 82). An RCT comparing ICS/LABA to

LABA allowed concomitant tiotropium use; a subgroup analysis showed a 28% reduction in

exacerbations comparing triple therapy to LABA plus LAMA(13). RCTs with triple therapy

in a single inhaler are ongoing, and will provide relevant data.

Non-ICS anti-inflammatory therapies: is anything useful?

The PDE4 inhibitor roflumilast has broad anti-inflammatory effects on different cell types

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(83). Roflumilast reduces exacerbation rates in COPD patients with chronic bronchitis, severe

airflow obstruction and a previous history of exacerbations(84) (85). This precision medicine

approach (3) targets a subgroup most likely to benefit. The biological rationale for this

differential effect remains unclear, and the nature of this effect is under evaluation(86).

Roflumilast improves FEV1 by approximately 50 – 80 mls in COPD patients(87, 88), but

without consistent benefits on symptoms (85, 88). Roflumilast can cause nausea, reduced

appetite, gastrointestinal disturbance and weight loss, so it is usually prescribed after better

tolerated inhaled treatments. A recent RCT confirmed that roflumilast decreased

exacerbations in COPD patients with chronic bronchitis on multiple inhaled medications(88),

and in real life roflumilast may decrease readmission rates in patients hospitalized for

COPD(89). Further work is needed to improve our understanding of the narrowly defined

patient populations where the clinical benefit of roflumilast is greatest, and attempts at

altering the dosage regimen to minimise side effects are ongoing(90).

Macrolides have immunomodulatory and antibacterial effects(91, 92). Two systematic

reviews of COPD RCTs confirmed a significant reduction in exacerbation rates with

macrolide therapy(93, 94). The most compelling data are for azithromycin therapy(95, 96),

although the optimal dosage is unclear, as daily and three times weekly dosing both

demonstrate efficacy(91). The patient population most likely to benefit has not been

identified(94). A post hoc analysis of the largest trial suggests an increased likelihood of

benefit in older patients with milder disease, and ex-smokers(97). The potential risks include

hearing loss(95) and prolonged QTc interval, raising concerns about cardiovascular

safety(98). Population-based studies have provided contradictory evidence regarding

cardiovascular safety (99, 100). Some have suggested that chronic macrolide therapy be

avoided in COPD patients at increased risk for arrhythmia(91, 98). Long-term azithromycin

therapy may result in new azithromycin resistant nasopharyngeal bacterial strains(95), and

cause increased azithromycin resistance in sputum bacterial isolates after just 3 months

treatment(101). A practical approach is to use macrolides in patients with ongoing

exacerbations despite triple therapy (96). However, this strategy does not target a likely

responder subgroup, or address concerns regarding antibiotic resistance.

RCTs evaluating mucolytics have varied greatly in their inclusion criteria (e.g. presence of

chronic bronchitis, use of inhaled treatments) and exacerbation definition. Nevertheless, a

systematic review suggests an effect on exacerbation reduction(102). Important questions

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remain regarding the effect of mucolytics in non-Asian populations(103), at varying

doses(104), and when associated to optimal concomitant therapies(105).

Personalised therapy – the future

An “FEV1-free” approach appears reasonable (provided that the diagnosis is confirmed using

spirometry), targeting pharmacotherapy towards symptoms (impact) and exacerbations

(activity). These are clinically recognisable treatable traits(106). Personalised approaches

targeting uncontrolled treatable traits can be further developed to include biomarker

measurements that provide information on underlying mechanisms (endotypes) and / or

disease activity. The historic and current approaches to COPD pharmacotherapy have used

FEV1 and clinical phenotyping respectively to guide treatment choices(5); Figure 3

summarises the evolution to a more personalised approach based on treatable traits plus

biomarkers.

Let us consider the example of persistent bacterial colonisation (an endotype) associated with

increased exacerbations (clinical phenotype, disease activity marker and treatable trait);

biomarker development to identify patients who would respond best to pharmacotherapies

such as macrolides would be of value. Similarly, identifying patients with repeated

exacerbations of a specific endotype (e.g. bacterial infection vs eosinophilic inflammation)

may allow more effective targeting of preventive treatments (i.e., bronchodilators ±

macrolides vs ICS-containing regimen). This may prove difficult since exacerbation

mechanisms can change from one exacerbation to the next. Another example is emphysema

(clinical phenotype and treatable trait); the development of biomarkers, possibly sRAGE(40),

may identify patients with greater disease activity that would benefit from future

pharmacological treatments targeting specific mechanisms (endotypes) involved in tissue

destruction.

COPD RCTs have not generally enrolled GOLD stage I patients (FEV1>80% predicted).

There is a high symptom burden in some GOLD I patients(107), and some smokers without

airflow obstruction(108). The efficacy of COPD treatments within this subgroup should be

addressed to develop personalised approaches.

The new inhaled therapies for COPD patients in recent years have been confined to existing

classes (LAMA, LABA, ICS). While it is disappointing that no novel classes have been

introduced, there is scope to develop a more personalised use of these existing medicines

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within our current practice. This is helped by evidence from head-to-head studies of different

classes(29, 72, 73, 78, 79), which are changing the way that we view bronchodilators and

ICS. New evidence suggesting that LABA/LAMA combinations may be more effective than

ICS/LABA for exacerbation prevention make the differential diagnosis between asthma and

COPD even more important(29), since ICS remains the cornerstone of asthma maintenance

therapy. Physicians should not label a patient as having asthma-COPD overlap without

performing the required investigations.

In the near future, we need measurements of endotypes and disease activity for the

development of COPD drugs with novel mechanisms of action. These drugs will likely only

show a satisfactory benefit versus risk ratio in narrowly defined subgroups, and we need to

develop the tools to define these subgroups.

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Figure Legends

Figure 1. FEV1 free approach to COPD pharmacotherapy; the assessment of

exacerbations and symptoms (A/B/C/D) guides pharmacotherapy. C&D = frequent

exacerbators currently defined as ≥ 2 exacerbations requiring antibiotics and / or oral

corticosteroids, or one hospitalisation, in the last year.

Figure 2. The relationships between components of COPD. Severity, (disease) activity

and impact are components of COPD; severity and activity determine the level of impact on a

patient. Disease activity drives disease progression, which worsens severity

Figure 3. Changing approaches to COPD pharmacotherapy. GOLD 2006 recommended

an FEV1 based approach for assessment and treatment, while GOLD 2011 recommended a

clinical phenotyping approach. In the future, treatable traits may be used, with endotype and /

or disease activity biomarkers.

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