LE BASI DELL’USO DEGLI ICS/LABA NELLA BRONCOPNEUMOPATIA LE BASI DELL’USO DEGLI ICS/LABA NELLA BRONCOPNEUMOPATIA CRONICA OSTRUTTIVACRONICA OSTRUTTIVA

GIAN GALEAZZO RIARIO SFORZAGIAN GALEAZZO RIARIO SFORZA

PNEUMOLOGIA RIABILITATIVAPNEUMOLOGIA RIABILITATIVAA.O. ISTITUTI CLINICI DI PERFEZIONAMENTO - MILANOA.O. ISTITUTI CLINICI DI PERFEZIONAMENTO - MILANO

COPD Management

What guidelines suggest

ICS/LABA combination therapy

ICS/LABA drawbacks

Which ICS/LABA?

Which COPD patient will benefit from ICS?

Agenda

Disease Management should now be focusing on 2 key areas

1.1. Reducing Symptoms Reducing Symptoms 2.2. Reducing RiskReducing Risk.

COPD Management

Pharmacologic treatment is used to:

Reduce Symptoms

Reduce frequency and severity of exacerbations

Improve health status

Improve exercise tolerance

GOLD 2014

Disease management:Pharmacologic Treatment

Pharmacologic options for COPD

COPD Management

What guidelines suggest

ICS/LABA combination therapy

ICS/LABA drawbacks

Which ICS/LABA?

Which COPD patient will benefit from ICS?

Agenda

National Institute for Health Care and Excellence

National Institute for Health and ClinicalExcellence. NICE clinical guideline 101.

Ann Intern Med. 2011;155:179-191.

Recommendation 5: clinicians may administer

combination inhaled therapies (LAMA, LABA or ICS) for

symptomatic patients with stable COPD and FEV<60%symptomatic patients with stable COPD and FEV<60%

predicted.

(Grade: weak recommendation, moderate-quality evidence)

Nelle persone con BPCO, sintomatiche nonostante l’uso regolare di broncodilatatori a lunga durata d’azione, con VEMS o FEV1 pre-broncodilatatore < FEV1 pre-broncodilatatore < 60%60% del valore teorico e storia di frequenti riacutizzazioni (2/anno), considerare l ’ associazione LABA + CSI.

L’utilizzo della combinazione fissa può migliorare in modo significativo l’aderenza della persona alla terapia.

Linee Guida AGENAS

The combination ICS + LABA or LAMA was

recommended as first choice in patientsrecommended as first choice in patientsgroup C and Dgroup C and D

Global initiative for chronic Obstructive Lung Disease

GOLD 2014Combined assessment of COPD

Adapted from GOLD 2014

Treatment OptionsTreatment Options

Less symptomsHigh risk

Less symptomsHigh risk

MMRC 01 CAT <10

GOLD 3

GOLD 4

First Recommended choice:•ICS + LABA or• LAMA

Alternative choice: • LABA and LAMA Or• LABA and PDE4-inh•LAMA and PDE4-inh

Other Possible Choices*: •SABA and/or SAMA• Theophylline

Adapted from GOLD 2014*Other Possible Choices can be used alone or in combination with other options in the First and Second columns

≥1 Or ≥2 leading to hospital admission

Patient Type (C)

Treatment OptionsTreatment Options

More symptomshigh risk

More symptomshigh risk

MMRC ≥2CAT ≥10

GOLD 3

GOLD 4

First Recommended choice: • ICS + LABA And/ or • LAMA

Alternative choice: • ICS + LABA and LAMA or • ICS+LABA and PDE4-inh. or• LABA and LAMA or• LAMA and PDE4-inh

Other Possible Choices*: • Carbocysteine• SABA and/or SAMA• Theophylline

Adapted from GOLD 2014*Other Possible Choices can be used alone or in combination with other options in the First and Second columns

≥1 Or ≥2 leading to hospital admission

Patient Type (D)

COPD Management

What guidelines suggest

ICS/LABA combination therapy

ICS/LABA drawbacks

Which ICS/LABA?

Which COPD patient will benefit from ICS?

Agenda

The LABA/ICS combination addresses the multicomponent nature of COPD more than does LABA or ICS treatment alone.

Cazzola M, Dahl R. CHEST 2004; 126:220–237

A I R F L O W L I M I T A T I O N

ICS/LABA vs. LABA monotherapy

Significant improvement in lung function

Significantly improves quality of life

Significant reduction in the rate of exacerbations

Combination therapy ICS/LABA improves lung function (TORCH)

The FORWARD study: Adjusted mean change from baseline in pre-dose morning FEV1

Respir Med. 2014 Aug;108(8):1153-62.

The pre-dose morning FEV1 increase from baseline to Week 12 was significantly larger in the beclomethasone/formoterol (BDP/FOR) group.

BDP/FOR

FOR

Cochrane Database Syst Rev. 2014;3, CD010844

Trough forced expiratory volume in one second (FEV1)

change from baseline—six-month and 12-month class results.

Combination therapy ICS/LABA significantly improves quality of life (TORCH)

St George's Respiratory Questionnaire (SGRQ) change from baseline—six-month and 12-month class results.

Cochrane Database Syst Rev. 2014;3, CD010844

Combination therapy ICS/LABA reduces the rate of exacerbations requiring systemic corticosteroids over three years (TORCH)

Annual exacerbation rates on selected randomized clinical trials

Current Drug Targets, 2013, Vol. 14, No. 2

Respir Med. 2014 Aug;108(8):1153-62.

The FORWARD study: Kaplan-Meier plot of time to first COPD exacerbation

• Beclomethasone/formoterol (BDP/FOR) reduced the adjusted exacerbation rate ratio by 28%.

• ICS/LABA combination therapy is more effecting in reducing exacerbation in severe COPD patients over LABA alone.

• This demonstrates the antiinflammatory effect of ICS, suggesting also a complementary and synergistic interaction at the molecular level.

BDP/FOR

FOR

When added to LABA in COPD,ICS reduce exacerbations only in patients with FEV1 ≤ 40%.

Puhan MA, et al. BMC Medicine 2009, 7:2

N Engl J Med Oct 2, 2014;371:1285-94.

Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD

Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM)

Combination therapy ICS/LABAversus LABA monotherapy

COPD Management

What guidelines suggest

ICS/LABA combination therapy

ICS/LABA drawbacks

Which ICS/LABA?

Which COPD patient will benefit from ICS?

Agenda

Compared to no treatment with ICS, ICS use was associated with a significant, potentially dose-related increase in risk of pneumonia in patients with COPD

Inhaled corticosteroid use in patients with chronic obstructive pulmonary disease and the risk of pneumonia: a retrospective claims data analysis International Journal of COPD 2013:8 295–304

Inhaled corticosteroids in COPD and the risk of serious pneumonia

Thorax 2013;68:1029-1036

ICS had no impact on hospitalisation for community-acquired pneumonia, and had no association with ICU admission, days-to-clinical recovery or mortality.

Almirall J, et al. PLoS ONE 2013 8(9): e73271.

Relationship between inhaled steroids and Community-Acquired Pneumonia

ICS/LABA had the lowest risk of mortality when compared with placebo, tiotropium or LABA only

Thorax 2013 Jan;68(1):48-56

COPD Management

What guidelines suggest

ICS/LABA combination therapy

ICS/LABA drawbacks

Which ICS/LABA?

Which COPD patient will benefit from ICS?

Agenda

Clin Ther 2010 Jul;32(7):1320-8.

Relative effectiveness of budesonide/formoterol and fluticasone propionate/salmeterol

• Patients treated with BUD/FM were less likely to have ED visits and hospitalizations for COPD and used fewer doses of anticholinergic medication in the year after treatment initiation.

• However, due to the observational nature of the study design, we cannot conclude with certainty that the medication was the only factor responsible for the observed differences.

Rapid onset of bronchodilation with formoterol/beclomethasone and formoterol/budesonide as compared to formoterol alone in patients with COPD Cazzola M, et al. Pulm Pharmacol Ther. 2011;24(1):118–22

• Rapid effect of the inhaled corticosteroid component when combined with formoterol.

• Onset of bronchodilation of formoterol/beclomethasone (Form/BDP) and formoterol/budesonide (Form/Bud) are similar and greater than formoterol alone.

The efficacy and safety of the novel once-daily combination of FF/VI 100/25 mcg in patients with moderate to very severe COPD over 12 weeks is not significantly different to that of the currently available FP/SAL 500/50 mcg twice daily dose.

Agustì A, et al. Eur Respir J 2014; 43: 763–772

A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD

CS corticosteroid,

CV cardiovascular,

FF fluticasone furoate,

LRTI lower respiratorytract infection,

PL placebo,

VI vilanterol,

ø indicates <1 %

Adverse events of special interest with once-daily fluticasone furoate/vilanterol compared with individual components and placebo in patients with moderate to severe COPD

Drugs (2014) 74:1509–1522

International Journal of COPD 2012:7 73–86

Efficacy and safety characteristics of mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination in subjects with moderate to very severe COPD

Conclusion of ICS/LABA choice

Because there are insufficient trials of head-to-head comparison design, adequate duration (>12 weeks) or with clinically relevant outcomes, it is currently it is currently difficult to recommend any of ICS/LABA difficult to recommend any of ICS/LABA combination over anothercombination over another

Curr Respir Care Rep (2014) 3:121–132

COPD Management

What guidelines suggest

ICS/LABA combination therapy

ICS/LABA drawbacks

Which inhaled corticosteroid?

Which COPD patient will benefit from ICS?

Agenda

• In many cases COPD is an outdated term that does not fully recognize the molecular and clinical heterogeneity of the disease.

• There is a strong need for going toward a new taxonomy and personalized approach to COPD

• Consequently, it is becoming increasingly important to Consequently, it is becoming increasingly important to identify those subjects with COPD with or without a identify those subjects with COPD with or without a favorable favorable response to ICSresponse to ICS

Moving from the Oslerian paradigm to the postgenomic

era: are asthma and COPD outdated terms?

Vanfleteren LEGW, et al. Thorax 2014;69:72–79.

Marc Miravitlles, et al. Prim Care Respir J 2013; 22(1): 117-121

A new approach to grading and treating COPD based on clinical phenotypes

• Infrequent exacerbators with either chronic bronchitis or emphysema

• Overlap COPD-asthma

• Frequent exacerbators with emphysema predominant

• Frequent exacerbators with chronic bronchitis predominant

Phenotypes of COPD

A new approach to grading and treating COPD based on clinical phenotypes

Prim Care Respir J 2013; 22(1): 117-121

There is room for the There is room for the use of ICS in COPD, use of ICS in COPD, at least in some at least in some subtypes of COPD subtypes of COPD

ConclusionsCazzola M, et al. Expert Opin. Pharmacother. (2013) 14(18):2489-2499