COPD MANAGEMENT 2014

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

Outlines

• Nonpharmacological management

• Anti-inflammatory drug

• New combination bronchodilator for COPD

NIV For Chronic Stable Severe COPD

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

GOLD IV, PaCO2 > 51.9 mmHg, pH > 7.35NPPV decrease 20% PaCO2, PaCO2 48.1 mmHgX 12 mon NPPV vs controlmean IPAP 21.6 mmHg EPAP 4.8 mmHg, RR 16unload respiratory muscle, reduce chronic hypercapnia

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

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

1-year mortality was 12% (12/102 pts) in the intervention group 33% (31 /93 pts) in the control group

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

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

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

SF-36

Anti-inflammation drug for COPD

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

FEV1 FVC

Diarrhea 6%ICS/LABA 59%LAMA 20%

Roflumilast 500 md/d 24 wk ACROSS study

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

Zheng JP et al. Lancet Respir Med 2014; 2: 187–94

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

Time to exacerbation events in patients receiving N-acetylcysteine or placebo

Time to fi rst exacerbation Time to second exacerbation

Time to 3rd AE

Zheng JP et al. Lancet Respir Med 2014; 2: 187–94

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)

NAC 600 mg BID x 1 yr ,120 ptsHIACE 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

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

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

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)

Proportion of patients free from acute exacerbations of COPD

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

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

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

COPD with 10-20% eosinophilic airway inflammationBenralizumab, 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 receptorbenralizumab reduces acute exacerbations of COPD in patients witheosinophilia 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

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, 2014http://dx.doi.org/10.1016/ S2213-2600(14)70187-0

Mean (SE) change from baseline in pre-bronchodilator FEV1

overall study population (A)

EO

> 200

EO

> 300

at 56 wk by EO

subgroup

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

ICS For COPD

Moderate to severe COPDHx of 1 exacerbationRun in Triple Tx TIO+FLU+SALThen 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 DisadvantagesContinue 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 No evidence of dose effect in some studiedbe reduced Reduced mortality only reported with

higher doses

Advantages and disadvantages of different therapeutic strategies regarding use of 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

GlycopyrroniumA 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).

• DOSAGE AND ADMINISTRATION

50 µg OD (inhalation using the Breezhaler ®)

• 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

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

QVA (INDA+GLYCO) VS TIO

mean difference for trough FEV1 (change from baseline) with 95% CIs of eligible studiescomparing QVA149 vs tiotropium.

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

Severe adverse event and severe CVS side effect QVA vs TIO

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

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

QVA 149 vs Glycopyrronium FEV1

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

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

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

QVA 149 vs Glycopyrronium Side effects

All treatments produced improvements in dyspnoea and health-related quality of lifeno 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

Clin Chest Med 2014; 35: 143–156

Response to SBA > 400 ml and 15%

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

COPD Asthma

Onset Midlife Early in life (often childhood)

Symptoms Slowly progressive

Dyspnea during exercise

Vary from day to day

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

Additional

features

Allergy, rhinitis and eczema

Family history of asthma

Inflammatory cells CD4+ (helper) T-lymphocytes and

eosinophils predominate1,2

Mast cells, lymphocytes, and macrophages

important, but less prominent1

CD8+ T-lymphocytes, neutrophils, and CD68+

monocytes/ macrophages predominate1,2

Eeosinophils play a minor role

(except for exacerbations)1

Response to

treatment

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

Systemic

inflammation

Bronchoconstriction

edema, mucus

Cardiovascular

comorbidity

Exacerbation

symptoms

Inflamed

COPD airways

Greater airway

inflammation

Viruses

BacteriaPollutants

Effects

Triggers

Reference. Wedzicha JA and Seemungal TA. Lancet 2007.

Expiratory flow

limitation

Dynamic

hyperinflation

Aeron SDBMJ 2014 349; g 537.

Acute management of moderate to severe exacerbationsof 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