title sub title Evidence-based Refinement of the Diagnosis and Management in Chronic Obstructive Pulmonary Disease

EXPERT MONOGRAPH ISSUE 22

Introduction

Chronic obstructive pulmonary disease (COPD) is characterised by progressive expiratory airflow limitation, resulting in the cardinal symptoms of dyspnoea, chest tightness, wheezing and cough. COPD is a leading cause

of morbidity and mortality worldwide and is expected to become the third leading cause of death by 2030.1

The decline in lung function results in significant dyspnoea and contributes to reduced physical activity in COPD patients. This can lead to a downward spiral of worsening symptoms and further inactivity,2 contributing to an increased risk of disability and death.3 Despite the progressive and incurable nature of COPD, various therapeutic options remain effective in reducing symptom burden, improving quality of life and preventing hospitalisation and mortality.

It is of vital importance to establish an accurate diagnosis of COPD at an early stage, as this allows for timely interventions that improve patient outcomes.

Take Home Messages

` An early diagnosis of COPD should be achieved through the broader use of spirometry, as this allows for differentiation between COPD and asthma.

` Non-pharmacological therapy is an essential component of COPD treatment and has well-established benefits.

` Dual bronchodilation (with a LAMA and a LABA) is superior to a LABA and ICS combination, as there is an improvement in lung function and a reduction in exacerbations.

` The National COPD-X Guidelines recommend ICS use in moderate to severe COPD only if there are frequent exacerbations (an FEV1 less than 50% of predicted, with two or more exacerbations in the preceding 12 months, and only as an add-on therapy to a LAMA and/or LABA).

` Given the significant systemic and local side-effects associated with long-term ICS use, appropriate withdrawal of ICS in COPD patients who are unlikely to benefit from them should be considered.

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DR PHILIP LEE BScMed MBBS (Hons) UNSW FRACP

Dr Philip Lee is a consultant in Respiratory and Sleep Medicine at St George Hospital. He has received local and international awards for his research work with continuing clinical and research interests in COPD, respiratory failure, non-invasive ventilation and sleep medicine. He is an expert advisor for Research Review Australia in COPD and has been an invited speaker at various local meetings. In 2016, Dr Lee received the St George Individual Volunteer Achievement Award for his outstanding contribution to the community.

This article discusses the recent refinements to the diagnosis and management of chronic obstructive pulmonary disease.

title sub title

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Hormonal Contraception Trouble-shooting Part One: The Overweight Woman

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Diagnosis

COPD Versus Asthma: Identifying Patients at Risk of Chronic Obstructive Pulmonary Disease

Despite advancements in diagnostic tools and technologies, COPD remains underdiagnosed and is often misdiagnosed as asthma.4,5 Careful differentiation between COPD and asthma is important as fundamental differences in the underlying pathophysiology significantly impact the disease management.6,7

Inflammation in COPD is characterised by increased infiltration of neutrophils, macrophages and CD8+ T cells, all of which may not be responsive to corticosteroid therapy. However, inflammation in asthma is typically associated with eosinophils, mast cells and CD4+ T cells and corticosteroids play an essential role in management.

Differentiation between COPD and asthma can be achieved via detailed assessment of clinical history. This should focus on the age of onset of symptoms, smoking status, precipitants, duration of symptoms, any other associated symptoms or signs, and relevant family history. Asthma should be considered in patients who have had respiratory symptoms beginning in childhood, in conjunction with clear precipitating factors and allergies/atopy. COPD should be considered as a differential diagnosis in patients aged over 35 years who have a definite history of moderate to heavy smoking (including ex-smokers) with compatible symptoms (dyspnoea, cough and/or sputum production) that are not of sudden and recent onset.8,9

The following criteria should also be considered in formulating a working diagnosis of COPD:10

• Smoker or ex-smoker

• Current or past occupational exposure to dust, gas or fumes

• Coughs several times most days

• Coughs up sputum on most days

• Out of breath more easily than others of a similar age

• Experiences chest tightness or wheeze

• Have frequent chest infections

Spirometry: ‘gold standard’ to confirm the diagnosis of COPD

A formal diagnosis of COPD is difficult to establish by clinical signs alone and can miss up to 50% cases of COPD.11 In the Australian GP setting, only 58% of patients treated for COPD have spirometry-confirmed diagnosis of COPD.12 Spirometry is the gold standard investigation to confirm the presence and severity of airflow obstruction for a correct diagnosis of COPD.8 It can differentiate between asthma and COPD via the estimation of bronchodilator response and allows an earlier COPD diagnosis, hopefully before patients develop irreversible symptoms.

COPD is defined as post-bronchodilator FEV1 less than 80% of that predicted for age and height, with evidence of airflow limitation (post-bronchodilator FEV1/FVC ratio less than 0.7), that is not fully or substantially reversible after bronchodilation. In patients with asthma, the airflow limitation is usually fully reversible after bronchodilation, signified by a fully reversible FEV1 response or an improvement in FEV1 of over 400mL.8,9 Of note, an FEV1 response between 200mL and 400mL, or greater than or equal to 12%, could be observed in both asthma and COPD. A thorough clinical assessment of history and presenting symptoms might allow clarification of the underlying diagnosis.

Updated Global Initiative for Chronic Obstructive Lung Disease classification

The Updated 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines address advancements in COPD management and incorporate evidence from recent landmark clinical trials. There are four categories: A, B, C and D, (see Table 1) based on symptoms and exacerbations.13

The Modified British Medical Research Council (mMRC) Dyspnoea Scale is used to quantify the effect of breathlessness on daily activities14 and the COPD Assessment Test (CAT) evaluates the impact of COPD on impairment of health.15

The severity of airflow obstruction via spirometry is no longer part of the severity classification system, due to discordant correlation with

Table 1: The Updated 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Classification System Based on Symptom Burden and Exacerbation History,13 with thanks for permission granted.

PATIENT GROUP SYMPTOMS

Lower symptom burden mMRC=0-1 CAT<10

Greater symptom burden mMRC≥2 CAT≥10

RISK

High risk of exacerbations ≥2 per year C DLow risk of exacerbations ≤1 per year A B

Evidence-based Refinement of the Diagnosis and Management in Chronic Obstructive Pulmonary Disease

quality of life and functional limitation. A thorough symptomatic assessment is advocated, as severity of airflow obstruction may not accurately predict the symptom burden or deficit in health-related quality of life.9

Therefore, a comprehensive assessment of COPD severity should take into account lung function, effect of symptoms on activities of daily living, level of breathlessness, concomitant co-morbidities and complications.

Management

Non-pharmacological interventions

The early implementation of non-pharmacological interventions can slow COPD progression and improve quality of life.8 These include smoking cessation, vaccination against influenza and pneumococcus, regular physical activity and pulmonary rehabilitation. These are highly recommended for all COPD patients regardless of disease severity.

Comprehensive management with non-pharmacotherapy strategies are again advocated in the latest GOLD Guidelines, in particular, the holistic management of other significant co-morbidities, such as cardiovascular disease, which may negatively impact on overall morbidity and mortality.13

Smoking cessation is the most significant intervention to halt lung function decline in COPD, reducing the rate of FEV1 decline to nearly the same levels as patients without COPD.16 It can also delay the onset of disability and preserve the remaining lung function.9 Direct smoking cessation advice from health professionals can increase quit rates. A brief three-minute counselling session encouraging a smoker to quit results in quit rates of 5% to 10%.17 If there were to be sufficient time and resources, long-term quit rates up to 25% could be achieved.18 COPD patients should also be offered treatment for nicotine dependence in conjunction with counselling.8,13

Vaccination reduces the health risks of influenza and pneumococcal infection. Annual influenza immunisation is recommended for all COPD patients.8,9 It reduces the risk of exacerbations, hospitalisation and death. Pneumococcal immunisation is also recommended for appropriate COPD patients. A booster after age 65 is advised if vaccination has not been given within the previous five years.8,9

Regular physical activity should be recommended for all COPD patients, including regular daily activity and pulmonary

rehabilitation.8 Low levels of physical activity and deconditioning are associated with reduced quality of life, disease progression, an increased risk of COPD exacerbations and mortality.8,19,20 Physical activity is the most important factor in determining the self-rated general health and health-related quality of life in patients who have COPD.21

Pulmonary rehabilitation is suitable for patients with chronic lung diseases, in particular, those reporting symptoms of dyspnoea/fatigue.8 It is, ideally, an effective multidisciplinary program aiming at reducing symptoms, enhancing participation in daily activities, improving exercise capacity and quality of life.8,22,23 Supervised exercise training is offered by such programmes as an essential component, along with breathing strategies to reduce dyspnoea, psychosocial support, nutritional advice, education and behavioural interventions.8,13,22,23 Irrespective of disease severity, all COPD patients benefit from pulmonary rehabilitation and maintenance of physical activity.8,13 The benefits of exercise include a reduction in symptoms (dyspnoea/fatigue), less depression and anxiety associated with COPD, fewer hospitalisations and reduced mortality.8,13

Although pulmonary rehabilitation should be offered to all patients with COPD, some medical conditions may preclude enrolment. These include advanced dementia or mental health diseases, uncontrolled or unstable cardiovascular comorbidities, musculoskeletal or neurological disorders which prevent exercise participation and patients who remain non-adherent to treatment recommendations.22,24

Pharmacological interventions

Various options of pharmacotherapy are available, including:

Long-acting bronchodilators

Long-acting bronchodilators achieve prolonged bronchodilation by promoting airway smooth muscle relaxation, resulting in significant long-term improvement in lung function, symptom relief (dyspnoea), quality of life as well as reducing the frequency of COPD exacerbations and lung hyperinflation.8,13

a. Long-acting ß2 adrenergic receptor agonists (LABAs)

These activate ß2-adrenergic receptors over airway smooth muscle surfaces, increasing cyclic AMP and inducing relaxation of the airway smooth muscle cells. This results in bronchodilation and lung function improvement.

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Evidence-based Refinement of the Diagnosis and Management in Chronic Obstructive Pulmonary Disease

b. Long-acting muscarinic receptor antagonists (LAMAs)

These block the action of acetylcholine on muscarinic receptors (M3) located on the surface of airway smooth muscle cells, resulting in reversal of bronchoconstriction.

Short-acting bronchodilators

a. Short-acting ß2 agonists (SABA) b. Short-acting muscarinic receptor antagonists (SAMAs)

Instead of regular use, these are commonly prescribed as a “rescue” medication to alleviate dyspnoea.8,13 The choice of the short-acting agent rests with patient preference. COPD patients should choose an agent which provides maximal symptomatic improvement, as suggested in a systematic review of SABAs (salbutamol), SAMAs (ipratropium) and SAMA/SABA combination, none of which revealed any major differences in treatment response.25

Inhaled corticosteroids

Cochrane systematic reviews of randomised controlled trials involving long-term (for greater than six months) inhaled corticosteroids (ICS) use in COPD showed small incremental benefits. These were improved lung function, quality of life and reduced exacerbations.8,13,26,27 However, ICS have no benefit in COPD mortality and no effect on lung function decline.26 Unlike asthma, ICS monotherapy is not indicated in patients with COPD and should only be given in combination with a LABA.

Updated GOLD Treatment Recommendations

The latest GOLD Guidelines suggest COPD treatment should be based on symptom burden and exacerbation history, with individualised pharmacotherapy targeted at GOLD grades A to D respectively (see Figure 1).13

What are the changes?

In Group C and D patients, a LABA and ICS combination was a first line option for treatment escalation in the 2016 GOLD Guidelines. The latest Guidelines recommend escalation to a LAMA and LABA combination prior to initiating ICS therapy. Groups A and B patients should not be given ICS treatment. Inhaled corticosteroids should no longer be used as monotherapy in COPD.13

From an Australian perspective, the Pharmaceutical Benefits Advisory Committee (PBAC) has considered the report on the post-market review of COPD medicines and advised the Minister in August 2017 of the proposed changes.28 These changes will positively impact long-term COPD management by ensuring that treatment is in-line with international guidelines:

• The addition of PBS restriction notes should confirm that a diagnosis of COPD by spirometry and that inhaler device technique has been checked.

• That the current PBS requirement in the LAMA and LABA PBS

Evidence-based Refinement of the Diagnosis and Management in Chronic Obstructive Pulmonary Disease

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Group C Group D

Group A Group B

LABA+ICSLAMA+LABA

LAMA+LABA+ICS

LAMA+LABA

LAMA LAMA+LABA LABA+ICS

Consider roflumilast if FEV1 <50% pred and patient has

chronic bronchitisConsider macrolide(in former smokers)

A bronchodilator

Continue, stop or try alternative class of bronchodilator

Furtherexacerbation(s)

Furtherexacerbation(s)

Furtherexacerbation(s)

Persistentsymptoms/

furtherexacerbation(s)

Evaluate effect

Preferred Treatment

Persistentsymptoms

LAMA

A long-acting bronchodilator (LABA or LAMA)

Figure 1. Pharmacotherapy algorithms by GOLD grade (reproduced with thanks for permission granted, from GOLD 2017, Fig. 4.1, p85).13

LAMA LAMA/LABA

Please review Product Information before prescribing. Full Product Information is available at www.boehringer-ingelheim.com.au/PI. Further information is available from Boehringer Ingelheim Pty Ltd.

SPIOLTO Respimat PBS Information: Authority required (STREAMLINED). Chronic obstructive pulmonary disease (COPD). Refer to PBS schedule for full authority information.

SPIRIVA Respimat PBS Information: Restricted benefit. Bronchospasm and dyspnoea associated with chronic obstructive pulmonary disease.

MINIMUM PRODUCT INFORMATION (COMBINED – COPD). SPIRIVA® RESPIMAT® (tiotropium bromide) solution for inhalation 2.5 microgram/actuation and SPIOLTO® RESPIMAT® [tiotropium (as bromide monohydrate)/olodaterol (as hydrochloride)] solution for inhalation 2.5 micrograms/2.5 micrograms. INDICATIONS: SPIRIVA RESPIMAT: Long term maintenance treatment of bronchospasm and dyspnoea associated with chronic obstructive pulmonary disease (COPD). Prevention of COPD exacerbations. SPIOLTO RESPIMAT: Once-daily maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. CONTRAINDICATIONS: SPIRIVA RESPIMAT and SPIOLTO RESPIMAT: Hypersensitivity to tiotropium bromide, olodaterol (SPIOLTO only), atropine or its derivatives, or to any of the excipients. PRECAUTIONS: SPIRIVA RESPIMAT and SPIOLTO RESPIMAT: Should not be used: more frequently than once daily; for relief of acute symptoms, treatment of acute episodes of bronchospasm, immediate hypersensitivity reactions, paradoxical bronchospasm, narrow-angle glaucoma, prostatic hyperplasia, bladder neck obstruction, urinary retention, micturition difficulties, recent myocardial infarction (<6 months for SPIRIVA, <12 months for SPIOLTO), unstable or life-threatening cardiac arrhythmia within past year, hospitalisation for heart failure within past year, moderate to severe renal impairment (CrCL ≤ 50 mL/min), pregnancy, lactation and children. Avoid solution or mist entering eyes. SPIRIVA RESPIMAT: Should not be used for: first-line treatment for asthma, dry mouth. SPIOLTO RESPIMAT: Should not be used: in treatment of asthma (LABAs may increase the risk of asthma-related hospitalisations and death); initiated in acutely deteriorating COPD, severe hepatic impairment, convulsive disorders, thyrotoxicosis, QT interval prolongation, unusual responsiveness to sympathomimetic amines; increases in pulse rate, blood pressure and/or symptoms of clinically significant cardiovascular effect, paroxysmal tachycardia (>100 beats per minute), hypokalaemia, hyperglycaemia. INTERACTIONS: SPIRIVA RESPIMAT and SPIOLTO RESPIMAT: Co-administration with anticholinergic drugs. SPIOLTO RESPIMAT: Co-administration with adrenergic agents, xanthine derivatives, steroids, non-potassium sparing diuretics, beta-blockers, MAO inhibitors, tricyclic antidepressants, QTc interval prolonging drugs, LAMAs, LABAs. ADVERSE EFFECTS: SPIRIVA RESPIMAT: Common: Dry mouth, usually mild. SPIOLTO RESPIMAT: Very common: nasopharyngitis. Common: pneumonia, bronchitis, influenza, urinary tract infection, sinusitis, cough, dyspnoea, back pain, dry mouth. Others, see full PI. DOSAGE: SPIRIVA RESPIMAT: For oral inhalation. 5 μg tiotropium given as two puffs once daily, at the same time each day. SPIOLTO RESPIMAT: For oral inhalation. 5 μg tiotropium and 5 μg olodaterol given as two puffs once daily, at the same time each day. Do not exceed recommended dose. Cartridges to be used only with RESPIMAT inhaler. January 2017. References: 1. SPIRIVA Respimat approved Product Information (13 September 2016). 2. SPIOLTO Respimat approved Product Information (10 June 2015). 3. Lung Foundation Australia. Stepwise management of stable COPD (August 2017). ®Registered trademark. Boehringer Ingelheim Pty Ltd. ABN 52 000 452 308. 78 Waterloo Road, North Ryde, NSW 2113. AUS/SPRES-181093i. McCann Health BOEH13585M. MARCH 2018.

LABA, long-acting β2-adrenergic agonist; LAMA, long-acting muscarinic antagonist.

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restrictions (to stabilise patients on both individual monotherapy inhalers before commencing a fixed-dose combination of LAMA and LABA) should be removed.

• The PBAC noted that there appears to be a high rate of initiation with an ICS and LABA combination in COPD and this is inconsistent with clinical guidelines. Therefore, the PBAC have recommended that the PBS restriction level be increased to Authority Required (Streamlined) for ICS and LABA combination inhalers that have dual listings on the PBS for the treatment of COPD and asthma.

Periodic review of inhaler device technique

The majority of pharmacological agents in COPD are delivered via inhalers. Previous studies have shown that up to 94% of COPD patients use their inhaler device incorrectly.29,30 Clinicians should demonstrate appropriate inhaler techniques to patients via a placebo device. All COPD patients should have their inhaler technique and treatment adherence reviewed on a regular basis during each clinical visit.9 It would be prudent to actively involve the patients, ensuring that they are able to demonstrate correct inhaler technique independently, identifying potential mistakes and repeating the process until patients are familiar with the device. Healthcare professionals and patients should be encouraged to access helpful educational resources from the Lung Foundation

Australia8, 31 and NPS MedicineWise to improve COPD management.

Role of dual bronchodilatation (LAMA and LABA)

In accordance with international guidelines, long-acting bronchodilators (LAMA and LABA) either as monotherapy or fixed-dose combination, should remain the cornerstone of maintenance therapy across all stages of COPD.8,13,31 Pharmacotherapy should be administered in a stepwise manner to control dyspnoea, to reduce the frequency of exacerbations and to maintain functional capacity in symptomatic COPD patients.9,31

Currently, the Pharmaceutical Benefits Scheme (PBS) stipulates that COPD patients should be stabilised on both individual monotherapy (LAMA and LABA) inhalers before commencing a fixed dose combination LAMA and LABA therapy. The PBAC recommended uplifting this restriction. The PBAC also recommended adding PBS restriction notes to check inhaler device technique and to confirm a diagnosis of COPD with spirometry.

These changes are necessary as there is demonstrated efficacy and safety of fixed dose combination LAMA and LABA use in COPD and the potential benefit of synergistic improvement of bronchodilation.32 Recent studies showed that a fixed dose combination of LAMA and LABA are superior to that of LABA and ICS in reducing the annual rate of COPD exacerbations,33 and it

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LABA, long-acting β2-adrenergic agonist; LAMA, long-acting muscarinic antagonist.

References: 1. SPIOLTO Respimat approved Product Information (10 June 2015). 2. Therapeutic Goods Association eBusiness Services. Australian Government Department of Health and Ageing. www.ebs.tga.gov.au (accessed 27 February 2018). TMTrademark. ®Registered trademark. Boehringer Ingelheim Pty Ltd. ABN 52 000 452 308. 78 Waterloo Road, North Ryde, NSW 2113. AUS/SPRES-181093a. McCann Health BOCO13585M. MARCH 2018.

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Evidence-based Refinement of the Diagnosis and Management in Chronic Obstructive Pulmonary Disease

improved lung function to a significantly greater extent than did a LABA and ICS combination.34 Meanwhile, the recently revised 2017 COPD GOLD Guidelines advocate optimising bronchodilation with dual bronchodilatation (LAMA and LABA) before introducing ICS, except for patients with concomitant asthma.13

Relevant Clinical Trials (Dual Bronchodilatation)

LABA and LAMA versus LABA and ICS: (Improving lung function) The ENERGITO Study

A complete crossover study found that a once-daily LABA and LAMA combination therapy (olodaterol and tiotropium) significantly improved lung function over 24 hours, when compared to a twice-daily LABA and ICS therapy (salmeterol and fluticasone). This study researched moderate to severe COPD patients who had a paucity of recent exacerbations. These subjects were 40 years of age and older, current or ex-smokers, with a greater than 10-pack-year smoking history and a post-bronchodilator FEV1 greater than or equal to 30%, and less than 80%, of predicted.33

Patients received each of the four treatment combination doses for a six-week period in a randomised sequence; the treatment period was separated by a three-week wash-out period. The primary endpoint was met. Olodaterol/tiotropium (5/5 μg) improved FEV1AUC0-12 by 129mL when compared to salmeterol/fluticasone (50/500 μg twice daily) combination therapy (p<0.0001; 95% CI 107–150).

A significant 86mL improvement in FEV1 AUC0-24 was also observed with once daily olodaterol/tiotropium (5/5 μg), versus salmeterol/fluticasone (50/500 μg twice daily). Both options covered the full daily dosing period. The frequency of adverse events was similar among all treatment groups, and 30% to 37% of patients reported at least one adverse event while on treatment. In summary, dual bronchodilation with olodaterol and tiotropium may serve as a viable maintenance therapy in patients who have moderate to severe COPD, causing a significant improvement in lung function.

LABA and LAMA versus LABA and ICS (Reducing rate of COPD exacerbations): FLAME Study

A 52-week, double-blinded study found that a once-daily LAMA and LABA combination therapy (glycopyrronium/indacaterol) was superior to twice-daily LABA and ICS (salmeterol/fluticasone) in reducing the rate of all COPD exacerbations, prolonging the time to first exacerbation and improving quality of life. This study researched severe to very severe COPD patients who had a recent history of exacerbations. The subjects were 40 years of age or older, with an mMRC score equal to or greater than two, FEV1 25% to 60% of predicted and treated with systemic glucocorticoids, antibiotics or both, for at least one COPD exacerbation in the previous year.34

All patients first received inhaled tiotropium (18 μg) once-daily during a four-week run-in period. Tiotropium was then discontinued and the patients randomly assigned to glycopyrronium/indacaterol (50/110 μg, once daily), or salmeterol/fluticasone (50/500 μg twice daily), for 52 weeks. The primary endpoint was met. The glycopyrronium/indacaterol combination therapy was superior to salmeterol/fluticasone in reducing the annual rate of all COPD exacerbations by 11% (HR 0.89; 95% CI 0.83–0.96; p=0.003), and 17% for moderate to severe COPD exacerbations (HR 0.83; 95% CI 0.75–0.91; p<0.001).

The secondary endpoint of this trial was the time to first COPD exacerbation (71 days for glycopyrronium/indacaterol versus 51 days for salmeterol/fluticasone, p<0.001). Of note, patients on glycopyrronium/indacaterol took significantly longer (127 days) than the LABA and ICS combination group (87 days) to experience their first moderate to severe exacerbation (p<0.001).

Another secondary endpoint was quality of life, as measured by the St George’s Respiratory Questionnaire. There was an improvement in quality of life in 49% of COPD patients receiving glycopyrronium and indacaterol combination therapy, compared to 44% who had salmeterol/fluticasone (OR 1.30; P<0.001). Although the overall frequency of adverse events was similar between the two treatment

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Evidence-based Refinement of the Diagnosis and Management in Chronic Obstructive Pulmonary Disease

groups, pneumonia was noted in 4.8% of the salmeterol/fluticasone patients, versus 3.2% of the glycopyrronium and indacaterol patients (p=0.02).

In summary, glycopyrronium and indacaterol in combination was a safe option and reduced exacerbations in COPD patients when compared to salmeterol/fluticasone.

Appropriate use of ICS therapy in COPD

A study involving 400 Australian GPs who identified patients as having a diagnosis of COPD showed that approximately 70% of COPD patients on maintenance therapy were prescribed a LABA and ICS combination.35,36 Although ICS use in COPD has been shown to reduce the rate of exacerbations, it has only modest improvements in quality of life and lung function,8,13 and so the derived benefits should be carefully weighed against the potential risks.

Long-term ICS use may increase the risk of pneumonia, osteoporosis, diabetes, oropharyngeal candidiasis and cataracts in COPD patients.6,7,13 In COPD, inflammation is largely resistant to corticosteroid treatment.6

ICS should only be used in COPD patients at high risk of

exacerbations… as an add-on therapy in patients who continue to suffer

from exacerbations despite LAMA and LABA therapy.

The National COPD-X Guidelines recommend ICS use in moderate to severe COPD only if there are frequent exacerbations (an FEV1 less than 50% of predicted, with two or more exacerbations in the preceding 12 months, and only as an add-on therapy to a LAMA and/or LABA).8,9,31 This is in keeping with the recently updated International GOLD strategy, which stipulate that ICS should only be used in COPD patients at high risk of exacerbations, and who have at least two exacerbations (or one exacerbation necessitating hospitalisation), in the preceding 12 months. Again, ICS should be used as an add-on therapy in patients who continue to experience exacerbations despite LAMA and LABA therapy.13

Therefore, vigilant use of combination LABA and ICS is advocated for COPD patients with severe/very severe COPD (FEV1 less than 50% of predicted) and frequent exacerbations that have not been adequately controlled by long-acting bronchodilators (LABA and/or LAMA).13,31

Triple therapy and ICS withdrawal

Triple therapy (LABA/LAMA/ICS) is recommended in the GOLD Guidelines for a specific group of COPD patients who

experience recurrent exacerbations despite treatment with dual bronchodilatation (LAMA and LABA, the preferred initial therapy), or LABA and ICS (alternative initial therapy).13

Although triple therapy has been shown to further improve lung function, health status and exacerbation rate when compared to a LABA and ICS combination and LAMA monotherapy, the efficacy of triple therapy when compared to dual bronchodilation (LABA and LAMA) is, as yet, unknown.37 Currently, the option of fixed dose combination triple therapy is not available in Australia.

Given the significant systemic and local side-effects associated with long-term ICS use, in particular, an increased risk of pneumonia,13 appropriate withdrawal of ICS in COPD patients unlikely to be of benefit from them should be considered. A recent study of COPD patients with severe to very severe (FEV1 less than 50%) with a history of one or more exacerbations in the preceding year showed that ICS withdrawal from triple therapy was non-inferior to ICS continuation in reducing the risk of moderate or severe exacerbations.38

Conclusion

COPD results in significant disability and is associated with a high risk of mortality. An early diagnosis of COPD should be achieved through the broader use of spirometry, as this allows for differentiation between COPD and asthma.

Non-pharmacological therapy is an essential component of COPD treatment and has well-established benefits. Appropriate use of inhaled medications in accordance with current guidelines is strongly advocated. This will achieve optimal clinical outcome and improve the cost-effectiveness of COPD therapy.

Adherence and inhaler technique should be re-assessed regularly to ensure COPD patients can use their devices correctly.

There is evidence suggesting dual bronchodilation (with a LAMA and a LABA) is superior to a LABA and ICS combination, as there is an improvement in lung function and a reduction in exacerbations. Vigilance when using an ICS for patients with COPD is prudent, as long-term ICS use is associated with adverse health outcomes.

Declaration

Dr Philip Lee was commissioned by Healthed for this article. The ideas, opinions and information presented are solely those of the author. The advertiser does not necessarily endorse or support the views expressed in this article. The author declares no significant competing financial, professional or personal interests that might influence this article.

References

A list of references and further reading is included in the website version of this article. Go to www.healthed.com.au/monographs

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Evidence-based Refinement of the Diagnosis and Management in Chronic Obstructive Pulmonary Disease

Further Reading

Yang I et al. Lung Foundation Australia. The COPD-X Plan: Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease. Version 2.49, March 2017.

References

1. WHO. Chronic respiratory diseases, Burden of COPD. Available from: http://www.who.int/respiratory/copd/burden/en/index.html {Accessed 7 Dec 2017}.

2. Reardon JZ, Lareau SC, ZuWallack R. Functional status and quality of life in chronic obstructive pulmonary disease. Am J Med. 2006 Oct; 119(10 Suppl 1): 32-7.

3. Casaburi R. Activity promotion: a paradigm shift for chronic obstructive pulmonary disease therapeutics. Am Thorac Soc. 2011 Aug; 8(4): 334-37.

4. Tinkelman DG, Price DB, Nordyke RJ, Halbert RJ. Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over. J Asthma. 2006 Jan-Feb; 43(1): 75-80.

5. Walters JA, Walters EH, Nelson M, Robinson A, Scott J, Turner P et al. Factors associated with misdiagnosis of COPD in primary care. Prim Care Respir J 2011; 20: 396–402.

6. Barnes PJ. Inhaled Corticosteroids Are Not Beneficial in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2000 Feb; 161(2 Pt 1): 342–344.

7. Price D, Yawn B, Brusselle G, Rossi A. Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD. Prim Care Respir J. 2013 Mar; 22: 92–100.

8. Yang I et al. Lung Foundation Australia. The COPD-X Plan: Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease. Version 2.49, March 2017.

9. Abramson M et al. COPD-X concise guide for primary care. Brisbane: Lung Foundation Australia, 2016. Available from: http://lungfoundation.com.au/health-professionals/guidelines/copd/copd-x-concise-guide-for-primary-care/ {Accessed 7 Dec 2017}.

10. Lung Foundation Australia. Case finding algorithm for COPD. https://lungfoundation.com.au/wp-content/uploads/2014/02/LFA-COPD-Case-Finding-Algorithm-June-2017.pdf {Accessed 7 Dec 17}

11. Walters JA, Hansen EC, Walters EH, Wood-Baker R. Under-diagnosis of chronic obstructive pulmonary disease: a qualitative study in primary care. Respir Med. 2008 May; 102: 738–743.

12. Zwar NA, Marks GB, Hermiz O, Middleton S, Comino EJ, Hasan I et al. Predictors of accuracy of diagnosis of chronic obstructive pulmonary disease in general practice. Med J Aust. 2011 Aug; 195: 168–171.

13. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2017 Report). Chapter 6. Available from: http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/ {Accessed 11 Dec 2017}.

14. Fletcher CM (Chairman). Standardised questionnaire on respiratory symptoms: a statement prepared and approved by the MRC Committee on the Aetiology of Chronic Bronchitis (MRC breathlessness score). BMJ 1960; 2: 1665.

15. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009 Sep; 34(3): 648-54.

16. Scanlon P, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS et al. Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease. The Lung Health Study. Am Resp Crit Care Med. 2000 Feb; 161(2 Pt 1): 381–390.

17. Stead LF, Buitrago D, Preciado N, Sanchez G, Hartmann-Boyce J, Lancaster T. Physician Advice for Smoking Cessation. Cochrane Database Syst Rev. 2013 May; 5(5): CD000165

18. van Eerd EA, van der Meer RM, van Schayck OC, Kotz D. Smoking cessation for people with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016 Aug; (8): CD010744.

19. Decramer M. Tiotropium as essential maintenance therapy in COPD. Eur Resp Rev. 2006; 15: 51−57.

20. Welte T, Vogelmeier C, Papi A. COPD: early diagnosis and treatment to slow disease progression. Int J Clin Pract. 2015 Mar; 69: 336–349.

21. Arne M, Lundin F, Boman G, Janson C, Janson S, Emtner M. Factors associated with good self-rated health and quality of life in subjects with self-reported COPD. Int J Chron Obstruct Pulmon Dis. 2011; 6: 511−519.

22. Spruit M, Singh SJ, Garvey C, ZuWallack R, Nici L, Rochester C et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013 Oct; 188(8):e13-64.

23. Frith P. A manual for pulmonary rehabilitation in Australia. 2008.

24. Corhay JL, Dang DN, Van Cauwenberge H, Louis R. Pulmonary rehabilitation and COPD: providing patients a good

www.healthed.com.au Page 9

Evidence-based Refinement of the Diagnosis and Management in Chronic Obstructive Pulmonary Disease

environment for optimizing therapy. Int J Chron Obstruct Pulmon Dis. 2014; 9: 27-39.

25. Appleton S, Jones T, Poole P, Pilotto L, Adams R, Lasserson TJ et al. Ipratropium bromide versus short acting beta-2 agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006 Apr; (2): CD001387.

26. Yang IA, Clarke MS, Sim EH, Fong KM. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Jul; 7: CD002991.

27. Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Sep; 9: CD006829.

28. Pharmaceutical Benefits Advisory Committee. August 2017 PBAC Meeting – Positive Recommendations. Available from: http://www.pbs.gov.au/industry/listing/elements/pbac -meet ings /pbac -ou tcomes /2017-08 /pos i t i ve -recommendations-2017-08.pdf {Accessed 11 Dec 2017}.

29. Lavorini F, Magnan A, Dubus JC, Voshaar T, Corbetta L, Broeders M et al. Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD. Respir Med. 2008 Apr; 102: 593–604.

30. Melani AS, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011 Jun; 105: 930–938.

31. Lung Foundation Australia. Stepwise management of stable COPD. February 2016.

32. Calzetta L, Matera MG, Cazzola M. Pharmacological interaction between LABAs and LAMAs in the airways: optimizing synergy. Eur J Pharmacol. 2015 Aug; 761: 168–73.

33. Beeh KM, Derom E, Echave-Sustaeta J, Grönke L, Hamilton A, Zhai D et al. The lung function profile of once-daily tiotropium and olodaterol via Respimat is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler (ENERGITO study). Int J Chron Obstruct Pulmon Dis. 2016 Feb; 11: 193–205.

34. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016 Jun; 374(23): 2222-34.

35. Data on file: HCN 2015. Update on COPD and Asthma Diagnosis and Management Q1 2015. Data from Medical Director General Practice Research Network.

36. PBS post-market review of COPD medicines: ToR 5. May 2017.

Available from: www.pbs.gov.au/info/reviews/post-market-review-chronic-obstructive-pulmonary-disease {Accessed 11 Dec 2017}.

37. Calverley PMA, Magnussen H, Miravitlles M, Wedzicha JA. Triple Therapy in COPD: What We Know and What We Don’t. COPD. 2017 Dec; 14(6): 648-662. doi: 10.1080/15412555.2017.1389875. Epub 2017 Nov 9.

38. Magnussen H, Disse B, Rodriguez-Roisin R, Kirsten A, Watz H, Tetzlaff K et al. Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD. N Engl J Med. 2014 Oct; 371: 1285–1294.

www.healthed.com.au Page 10

Evidence-based Refinement of the Diagnosis and Management in Chronic Obstructive Pulmonary Disease