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“COPD and new treatment options: the role of primary care’’ Please use the dd month yyyy format for the date for example 11 January 2008. The main title can be one or two lines long. Professor of Primary Care Research Southampton University, UK ERS 2014

Disclosures Speaker’s honoraria: Astra Zeneca, Boehringer Inglehiem, Aerocrine, Teva and GSK. Advisory panels: Aerocrine, Almirall, Astra Zeneca, BI, Chiesi, GSK, MSD, Novartis Sponsorship: GSK, Astra Zeneca, Mundipharma, Aerocrine, BI If using a school logo, make sure that if you have a long page title, it does not encroach on the logo. Allow about 2cm around the logo. Run the page title onto two lines if necessary.

Role of Primary Care in COPD treatment Primary care has a central and fundamental role in COPD Most patients present initially to Primary Care for diagnosis and management Many patients are treated only in primary care Primary care decides on who needs specialist assessment Most exacerbations present to primary care Even those under specialist care need Intergrated Care: Coordination of care, co-morbidities

New Treatments for COPD What new treatment options do we have? Pharmacotherapy New drug classes, new versions of existing classes, new combinations New ways of using medicines- new GOLD strategy and risk stratification Non-pharmacological treatments: Smoking cessation, exposures, Pulmonary rehabilitation, vaccination, ventilatory support, surgery Management of co-morbidities

© 2014 Global Initiative for Chronic Obstructive Lung Disease Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: COPD Medications Beta2-agonists Short-acting beta2-agonists Long-acting beta2-agonists Anticholinergics Short-acting anticholinergics Long-acting anticholinergics Combination short-acting beta2-agonists + anticholinergic in one inhaler Combination long-acting beta2-agonists + anticholinergic in one inhaler Methylxanthines Inhaled corticosteroids Combination long-acting beta2-agonists + corticosteroids in one inhaler Systemic corticosteroids Phosphodiesterase-4 inhibitors © 2014 Global Initiative for Chronic Obstructive Lung Disease

© 2014 Global Initiative for Chronic Obstructive Lung Disease Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Phosphodiesterase-4 Inhibitors In patients with severe and very severe COPD (GOLD 3 and 4) and a history of exacerbations and chronic bronchitis, the phospodiesterase-4 inhibitor, roflumilast, reduces exacerbations treated with oral glucocorticosteroids. Oral, anti-inflammatory Always with a long acting bronchodilator Limited role in Primary Care © 2014 Global Initiative for Chronic Obstructive Lung Disease

New versions of existing treatments classes LABAs ‘Ultra-long acting’- once daily ? Incremental benefits over twice daily treatment LAMAs Now other drugs in class, once and twice daily ICS-LABA combination ICS Only licensed as combination therapy New molecule: FF, ?dose equivalence LABA-LAMA combinations ‘Dual bronchodilators’

New molecules for COPD New versions of old classes LAMA Umeclidinium Glycopyrronium Aclidinium LABA Vilanterol Indercaterol Olodaterol ICS Fluticasone Fuorate New versions of old classes Pharmacological differences In varying combinations- ICS- LABA, LABA-LAMA

How important are these to Primary Care? Always good to have more than one drug in class May be incremental benefits from new drugs in class Long duration of action, once daily dosing Potency Combinations simplify regimes, may lead to better adherence New devices and delivery systems may be easier to use However- by and large benefits are class effects New ways of using drug classes may be most important

Risk Symptoms (C) (D) (B) (A) ≥ 2 or > 1 leading to hospital Global Strategy for Diagnosis, Management and Prevention of COPD Risk Stratification in COPD (GOLD Classification of Airflow Limitation)) Risk (Exacerbation history) ≥ 2 or > 1 leading to hospital admission 1 (not leading to hospital admission) Symptoms (C) (D) (A) (B) CAT < 10 4 3 2 1 CAT > 10 mMRC 0–1 mMRC > 2

Therapy at Each Stage of COPD IV: Very Severe II: Moderate III: Severe I: Mild FEV1/FVC < 70% FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure FEV1/FVC < 70% 30% < FEV1 < 50% predicted FEV1/FVC < 70% 50% < FEV1 < 80% predicted FEV1/FVC < 70% FEV1 > 80% predicted Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) This provides a summary of the recommended treatment at each stage of COPD. Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Add long term oxygen if chronic respiratory failure. Consider surgical treatments

ICS + LABA or LAMA ICS + LABA and/or LAMA > 2 SAMA prn or SABA prn Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: Pharmacologic Therapy RECOMMENDED FIRST CHOICE C D GOLD 4 ICS + LABA or LAMA ICS + LABA and/or LAMA > 2 GOLD 3 Exacerbations per year A B GOLD 2 SAMA prn or SABA prn LABA or LAMA 1 GOLD 1 mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 © 2013 Global Initiative for Chronic Obstructive Lung Disease

Assess symptoms first (C) (D) (A) (B) If CAT < 10 or mMRC 0-1: Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD Assess symptoms first (C) (D) (A) (B) If CAT < 10 or mMRC 0-1: Less Symptoms/breathlessness (A or C) If CAT > 10 or mMRC > 2: More Symptoms/breathlessness (B or D) CAT < 10 CAT > 10 Symptoms Breathlessness mMRC 0–1 mMRC > 2 © 2014 Global Initiative for Chronic Obstructive Lung Disease

Assess degree of airflow limitation using spirometry Global Strategy for Diagnosis, Management and Prevention of COPD Assessment of COPD Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities Use history of exacerbations and spirometry. Two exacerbations or more within the last year or an FEV1 < 50 % of predicted value are indicators of high risk. Hospitalization for a COPD exacerbation associated with increased risk of death. © 2014 Global Initiative for Chronic Obstructive Lung Disease

COPD Assessment Test (CAT) or Clinical COPD Questionnaire (CCQ) Global Strategy for Diagnosis, Management and Prevention of COPD Assessment of COPD Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities COPD Assessment Test (CAT) or Clinical COPD Questionnaire (CCQ) mMRC Breathlessness scale © 2014 Global Initiative for Chronic Obstructive Lung Disease

Interpreting the score: <10: Low impact 10-20: Medium impact, room for improvement >20: High impact: increase therapy, consider referral

© 2014 Global Initiative for Chronic Obstructive Lung Disease Global Strategy for Diagnosis, Management and Prevention of COPD Modified MRC (mMRC)Questionnaire © 2014 Global Initiative for Chronic Obstructive Lung Disease

© 2014 Global Initiative for Chronic Obstructive Lung Disease Global Strategy for Diagnosis, Management and Prevention of COPD Assess Risk of Exacerbations To assess risk of exacerbations use history of exacerbations and spirometry: Two or more exacerbations within the last year or an FEV1 < 50 % of predicted value are indicators of high risk. One or more hospitalizations for COPD exacerbation should be considered high risk. © 2014 Global Initiative for Chronic Obstructive Lung Disease

What drugs are we using?

ICS use and GOLD recommendations (1) % Patients Patients (%) COPD = chronic obstructive pulmonary disease; GOLD = Global initiative for chronic Obstructive Lung Disease; ICS = inhaled corticosteroid; SABA = short-acting β2 agonist; SAMA = short-acting muscarinic antagonist In this study, Small et al. performed an analysis of data from the Adelphi Respiratory Disease Specific Programme (a large, multinational, cross-sectional survey, which generates real-world data based on actual clinical practice) to evaluate whether pharmacologic treatment patterns in the real world align with what is recommended for each of the four GOLD patient groups. The analysis was undertaken between June and September 2011 and collected data from primary and secondary care physicians and their patients (n=1,508) in France, Germany, Italy, Spain, the UK and USA. Only a small proportion of patients were receiving no treatment and these were confined to GOLD 2011 Group A (3% [1% of the total COPD study population]). Furthermore, use of relief medication only (SABA/SAMA) was more common in Group A compared with all other groups except Group C; however, the limited number of patients in Group C (n=13) precludes any meaningful interpretation of findings in that patient group. The high incidence of ICS use observed in this real-world population of COPD patients with Group A or B disease suggests that these patients are not being treated according to GOLD 2011 recommendations, which indicate that this treatment option should be reserved for patients with Group C or D disease. Reference Small M, Broomfield S, Higgins V. Quantification and treatment patterns of real-world patients classified by the GOLD 2011 strategy. Eur Respir J 2012;40(Suppl. 56):524s (Abstract P2876). A (n=152) B (n=739) C (n=13) D (n=604) Total COPD population (n=2,225) GOLD group Patients were assigned to GOLD groups based ion CAT score; COPD = chronic obstructive pulmonary disease; GOLD = Global initiative for chronic Obstructive Lung Disease; ICS = inhaled corticosteroid; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting β2 agonist; SAMA = short-acting muscarinic antagonist Small et al. Eur Respir J 2012 (Abstract P2876)

GOLD and primary care Problems with GOLD: Consistency- categories vary with tool used Ease of use in Primary Care Lack of contribution of known risk factors, e.g.smoking Risk in group B Comorbidities Risk stratification is however valid!

Asthma and COPD similarities and differences Postma D et al Clin Chest Med 2014

Using drugs better- Dual Bronchodilation ∆=200 mL, p<0.001 ∆=80 mL, p<0.001 1.50 ∆=90 mL, p<0.001 ∆=70 mL, p<0.001 ∆=130 mL, p<0.001 1.45 ∆=120 mL, p<0.001 ∆=130 mL, p<0.001 1.40 Trough FEV1 (L) 1.35 1.30 Trough FEV1 at Week 26 (the primary efficacy endpoint) was significantly improved with QVA149 compared with both indacaterol and glycopyrronium, with significant treatment differences of 70 mL and 90 mL, respectively (both p<0.001). QVA149 also provided significantly higher improvement in trough FEV1 compared with open-label tiotropium and placebo at Week 26, with treatment differences of 80 mL and 200 mL, respectively (p<0.001). All active treatments were associated with significantly improved trough FEV1 compared with placebo at Week 26 (p<0.001). Reference Bateman E et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J 2013. Epub ahead of print. 1.25 1.25 1.37 1.36 1.38 1.45 1.20 Placebo Open-label tiotropium 18 μg q.d. Glycopyrronium 50 μg q.d. Indacaterol 150 μg q.d. QVA149 110/50 μg q.d. Values are least-squares mean ± standard error Bateman et al. Eur Respir J 2013 (epub ahead of print)

So what’s new in pharmacotherapy No new classes (PDE4) Some new ‘within-class’ treatments and delivery systems Some new single-inhaler combinations (LABA-LAMA) New concepts : in assessing patients, in using treatments Better understanding of how to use and target treatments

Comorbidities and primary care

Psychological co-morbidity and respiratory symptoms Perception Behavior Over-use of rescue bronchodilators Non-compliance with regular medication At-risk behaviors (smoking, substance abuse) Poor self-management Biological effects- immunology and neurology

Understanding your patient- psychological co-morbidity

Conclusions Numerous new products for treating COPD in primary care, but few new classes Newer versions of exiting treatments may have some incremental benefits: More potent Longer lasting More convenient LABA-LAMA single-inhaler combinations available New strategies for directing treatment better

GOLD: recommendations for initial pharmacologic treatment Based on combined assessment of airflow limitation, symptoms and exacerbations (C) (D) GOLD 1 GOLD 2 GOLD 3 GOLD 4 ICS + LABA or LAMA ICS + LABA and/or LAMA ≥2 or ≥1 leading to hospital admission ICS+LABA and LAMA or ICS+LABA and PDE4-inh or LABA and LAMA or LAMA and PDE4-inh LABA and LAMA or LABA and PDE4-inh or LAMA and PDE4-inh No. of exacerbations/year GOLD classification of airflow limitation SABA or SAMA p.r.n.  LABA or LAMA 1 (not leading to hospital admission) LABA or LAMA or SABA and SAMA CAT = COPD Assessment Test; GOLD = Global initiative for chronic Obstructive Lung Disease; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; mMRC = modified Medical Research Council; PDE4-inh = phosphodiesterase 4 inhibitor; p.r.n. = pro re nata as needed; SABA = short-acting β2-agonist; SAMA = short-acting muscarinic antagonist Medications in each box are mentioned in alphabetical order and therefore are not necessarily in order of preference. Alternate choice medications (not shown) can be used alone or in combination with other options in the first or second choices. Current GOLD guidelines recommend a long-acting bronchodilator (LABA or LAMA) as a first-choice option for patients with COPD in groups B, C or D and as a second choice for patients in group A. For patients in groups B, C and D, a combination of a LABA and LAMA is included as a second-choice option. Reference Global initiative for chronic Obstructive Lung Disease (GOLD 2014). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated 2014. Last accessed 22 January 2014. http://www.goldcopd.org/uploads/users/files/GOLD_Report_2014.pdf LABA and LAMA  (A) (B) CAT ≥10 mMRC ≥2 CAT <10 mMRC 01 (Symptoms) (Breathlessness) Recommended first choice Alternative choice CAT = COPD Assessment Test; GOLD = Global initiative for chronic Obstructive Lung Disease LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; mMRC = modified Medical Research Council; PDE4-inh = phosphodiesterase 4 inhibitor; p.r.n. = pro re nata as needed SABA = short-acting β2-agonist; SAMA = short-acting muscarinic antagonist GOLD 2014