COPD MANAGEMENT 2014

Assistant Prof. Siwasak Juthong. M.D. Division of Respiratory and Respiratory Critical Care Medicine Faculty of Medicine Prince of Songkla University

Outlines • Nonpharmacological management • Anti-inflammatory drug • New combination bronchodilator for COPD

NIV For Chronic Stable Severe COPD

GOLD IV, PaCO2 > 51.9 mmHg, pH > 7.35 NPPV decrease 20% PaCO2, PaCO2 48.1 mmHg X 12 mon NPPV vs control mean IPAP 21.6 mmHg EPAP 4.8 mmHg, RR 16 unload respiratory muscle, reduce chronic hypercapnia Kohnlein T ,Lancet Respir Med 2014;2: 698 –705

Kaplan-Meier estimate of cumulative all-cause mortality during the fi rst year after randomisation (primary outcome)

hazard ratio 0.24 (95% CI 0.11–0.49; p=0.0004)

1-year mortality was 12% (12/102 pts) in the intervention group 33% (31 /93 pts) in the control group Kohnlein T ,Lancet Respir Med 2014;2: 698 –705

Changes from baseline in secondary quality of life outcomes (HRQL in patients with severe, stable COPD with or without additional long-term NPPV treatment) SF-36

Kohnlein T ,Lancet Respir Med 2014;2: 698 –705

Anti-inflammation drug for COPD

Roflumilast 500 md/d 24 wk ACROSS study

FEV1

FVC

Diarrhea 6% ICS/LABA 59% LAMA 20%

Zheng J et al. CHEST 2014; 145(1):44–52

Zheng J et al. CHEST 2014; 145(1):44–52

NAC 600 mg BID x 1 yr ,1,004 pts, multicenter PANTHEON study

Forest plot of exacerbations in all patients, and stratified by GOLD moderate and GOLD severe disease Zheng JP et al. Lancet Respir Med 2014; 2: 187–94

Time to fi rst exacerbation

Time to second exacerbation

1.16 exacerbations per patient-year in NAC (1.49 exacerbations per patient-year; risk ratio 0.78, 95% CI 0.67–0.90; p=0.0011)

Time to 3rd AE Time to exacerbation events in patients receiving N-acetylcysteine or placebo Zheng JP et al. Lancet Respir Med 2014; 2: 187–94

NAC 600 mg BID x 1 yr ,120 pts HIACE study

TSE HN et al .Chest 2014; 146(3): 611-623

Cumulative exacerbation frequencies over the 1-y study period TSE HN et al .Chest 2014; 146(3): 611-623

Proportion of exacerbation-free patients in the 1-y study period

TSE HN et al .Chest 2014; 146(3): 611-623

Antibiotic/Anti-inflammatory

COPD AE > 3/yr, 92 pts, add on to mainly (>90%) triple therapy Azithromycin 500 mg 3 time/wk x 12 mon

Uzun S et al.Lancet Respir Med 2014; 2: 361–68

Proportion of patients free from acute exacerbations of COPD

Rate ratio azithromycin vs placebo (0.58,95% CI 0.42–0.79; p=0.001)

azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0.58,95% CI 0.42–0.79; p=0.001) diarrhoea in the azithromycin group (nine [19%] pts vs one [2%] in the placebo group; p=0.015) Uzun S et al.Lancet Respir Med 2014; 2: 361–68

COPD with 10-20% eosinophilic airway inflammation Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. Interleukin-5 regulates the differentiation,proliferation, survival, and activation of eosinophils via the interleukin-5 receptor benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD? Phase II2, 101 COPD ,AE > 1, sputum eosinophil > 3% 50% triple Tx, LAMA 50% 100 mg benralizumab subcutaneously with 4 wk x 3 dose then with 8 wk x 5 Brightling CE et al. Lancet Respir Med 2014 Published Online September 8, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70187-0

Rate of annualised moderate and severe AECOPD at wk 56 (per-protocol population)

Brightling CE et al. Lancet Respir Med 2014 Published Online September 8, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70187-0

overall study population (A)

EO > 200

EO > 300

at 56 wk by EO subgroup

Mean (SE) change from baseline in prebronchodilator FEV1

Brightling CE et al. Lancet Respir Med 2014 September 8, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70187-0

ICS For COPD

Moderate to severe COPD Hx of 1 exacerbation Run in Triple Tx TIO+FLU+SAL Then 1) triple Tx TIO+FLU+SAL 52 wk 2) withdraw FLU +TIO+SAL

Magnussen H., et al. NEJM 2014 Sept DOI: 10.1056/NEJMoa1407154

Magnussen H., et al. NEJM 2014 Sept DOI: 10.1056/NEJMoa1407154

Add ICS to LABA in COPD base on symptomatic improvement, not for prevent exacerbation

Reilly JJ. NEJM 2014 Sept DOI: 10.1056/NEJMe1409219

Side-effects of inhaled corticosteroids in COPD and type of evidence

D Price et al. Prim Care Respir J 2013; 22(1): 92-100

Possible mechanisms of increased pneumonia risk with ICS in COPD

Finney L. et al. Lancet Respir Med 2014 Published Online September 18, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70169-9

Advantages and disadvantages of different therapeutic strategies regarding use of ICS in COPD Advantages

Disadvantages

Continue ICS

Reduce exacerbations, Increased pneumonia improve lung function, and health status Discontinue ICS Reduced risk of pneumonia Adverse eff cts reported with ICS withdrawal Change fluticasone Pneumonia risk might be Pneumonia risk might not be less with to budesonide less with budesonide budesonide Reduce dose of ICS Pneumonia risk might be reduced

No evidence of dose effect in some studied Reduced mortality only reported with higher doses

Finney L. et al. Lancet Respir Med 2014 Published Online September 18, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70169-9

Glycopyrronium A new long acting muscarinic antagonist (LAMA)

Seebri™ Breezhaler® Indication and dosage •

INDICATION once-daily maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).

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DOSAGE AND ADMINISTRATION 50 µg OD (inhalation using the Breezhaler ®)

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DESCRIPTION AND COMPOSITION Active substance – Each capsule contains 63 µg glycopyrronium bromide equivalent to 50 µg glycopyrronium. – The delivered dose* is equivalent to 44 µg glycopyrronium. Pharmaceutical form – 50 µg, inhalation powder hard capsules. – transparent orange capsules containing a white powder

* Delivered dose = the dose that leaves the mouthpiece of the Seebri Breezhaler inhaler

Clinical efficacy of LAMA in COPD

Khuder Alagha K, et al. Ther Adv Chronic Dis 2014, Vol. 5(2) 85–98

Combination bronchodilators

Mechanistic differences between bronchodilator agents for the management of COPD.

Barnes PJ et a. Academic Press, 2008

Rodrigo G, Plaza V. CHEST 2014; 146(2):309- 317

QVA (INDA+GLYCO) VS TIO

QVA 149 vs TIO improve FEV1 70 ml, decrease rescue med (0.6 puff/d) number needed to treat for benefit (NNTB) (NNTB =11) NNTB for SGRQ = 11

mean difference for trough FEV1 (change from baseline) with 95% CIs of eligible studies comparing QVA149 vs tiotropium. Rodrigo G, Plaza V. CHEST 2014; 146(2):309- 317

Severe adverse event and severe CVS side effect QVA vs TIO

Rodrigo G, Plaza V. CHEST 2014; 146(2):309- 317

QVA 149 vs Glycopyrronium FEV1

mean difference for trough FEV1 (change from baseline) with 95% CIs of eligible studies comparing QVA149 vs glycopyrronium

QVA 149 vs GLY improve FEV1 70 ml, decrease rescue med (0.59 puff/d) NNTB for SGRQ = 12 Rodrigo G, Plaza V. CHEST 2014; 146(2):309- 317

QVA 149 vs Glycopyrronium Side effects

A, Pooled relative risk for the number of patients with severe adverse events. B, Pooled relative risk for the number of patients with severe cardiovascular events, with 95% CIs of eligible studies comparing QVA149 vs glycopyrronium Rodrigo G, Plaza V. CHEST 2014; 146(2):309- 317

All treatments produced improvements in dyspnoea and health-related quality of life no signifi cant differences in symptoms, health status, or risk of exacerbation between UMEC plus VI and TIO

Lancet Respir Med 2014;2: 472–86

Serial spirometry on week 26 in the SHINE study. Serial spirometry was conducted in a subset of 294 patients

Annualised rate of COPD exacerbations over 64–76 weeks in the SPARK study by treatment group. Data are presented as rate reduction (95% CI). #: p50.0052; ": p50.0072; +: p50.096; 1: p50.038; e: p50.36; ##: p50.18; "": p50.0017; ++: p50.0012

Asthma COPD Overlap Syndrome

Response to SBA > 400 ml and 15%

Clin Chest Med 2014; 35: 143–156

Differential Diagnosis of COPD COPD and asthma are distinct conditions that can be differentiated from each other COPD

Asthma

Midlife

Early in life (often childhood)

Slowly progressive

Vary from day to day

Dyspnea during exercise

More common at night/early morning

Airflow limitation

Largely irreversible

Largely reversible

Main risk factors for development

Tobacco smoke and airborne pollutants

Exposure to allergens, infections, diet, tobacco smoke, socioeconomic status

Onset Symptoms

Additional features Inflammatory cells

Response to treatment

Allergy, rhinitis and eczema Family history of asthma CD4+ (helper) T-lymphocytes and eosinophils predominate1,2

CD8+ T-lymphocytes, neutrophils, and CD68+ monocytes/ macrophages predominate1,2

Mast cells, lymphocytes, and macrophages important, but less prominent1

Eeosinophils play a minor role (except for exacerbations)1

Gucocorticosteroids inhibit inflammation4

Glucocorticosteroids have little or no effect4

COPD, chronic obstructive pulmonary disease.

Reference. GOLD. 2013.

COPD Exacerbation Increase MI 1-5 d after AECOPD 2-3 times

Exacerbation triggers and effects Triggers

Viruses Pollutants

Bacteria

Effects

Inflamed COPD airways Greater airway inflammation

Systemic inflammation

Bronchoconstriction edema, mucus Expiratory flow limitation

Cardiovascular comorbidity

Exacerbation symptoms

Dynamic hyperinflation

Reference. Wedzicha JA and Seemungal TA. Lancet 2007.

Aeron SDBMJ 2014 349; g 537.

Acute management of moderate to severe exacerbations of chronic obstructive pulmonary disease

Conclusion • Bronchodilators the main drug for COPD • Bronchodilator before anti-inflammatory drug • NPPV improved mortality in severe COPD

Thank You for Your Attention