LE BASI DELL’USO DEGLI ICS/LABA NELLA BRONCOPNEUMOPATIA
CRONICA OSTRUTTIVA
G IAN G ALEAZZO R IARIO S FORZA
P NEUMOLOGIA RIABILITATIVA
A.O. I STITUTI C LINICI DI P ERFEZIONAMENTO - M ILANO

Agenda

 What guidelines suggest
 ICS/LABA combination therapy
 ICS/LABA drawbacks
 Which ICS/LABA?
 Which COPD patient will benefit from ICS?

 Disease Management should now be focusing on 2 key areas
1.
Reducing Symptoms
2.
Reducing Risk
.


 Reduce Symptoms
 Reduce frequency and severity of exacerbations
 Improve health status
 Improve exercise tolerance
GOLD 2014

Agenda
 COPD Management

 ICS/LABA combination therapy
 ICS/LABA drawbacks
 Which ICS/LABA?
 Which COPD patient will benefit from ICS?

National Institute for Health and Clinical
Excellence. NICE clinical guideline 101.

Ann Intern Med. 2011;155:179-191.
clinicians may administer combination inhaled therapies (LAMA, LABA or ICS) for 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 < 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.

The combination ICS + LABA or LAMA was recommended as first choice in patients group C and D

GOLD 2014
Combined assessment of COPD
Adapted from GOLD 2014

Patient Type (C)
First Recommended choice:
•
ICS + LABA or
•
LAMA
•
Alternative choice:
LABA and LAMA
Or
•
LABA and PDE4-inh
•
LAMA and PDE4-inh
GOLD 4
GOLD 3
Less symptoms
High risk
MMRC 0  1
CAT <10
Other Possible Choices*:
•
SABA and/or SAMA
•
Theophylline
*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
Adapted from GOLD 2014

Patient Type (D)
First Recommended choice:
•
ICS + LABA
And/ or
•
LAMA GOLD 4
Alternative choice:
•
ICS + LABA and LAMA or
•
ICS+LABA and PDE4-inh. or
•
LABA and LAMA or
•
LAMA and PDE4-inh
GOLD 3
More symptoms high risk
MMRC ≥2
CAT ≥10
Other Possible Choices*:
•
Carbocysteine
•
SABA and/or SAMA
•
Theophylline
*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
Adapted from GOLD 2014

Agenda
 COPD Management
 What guidelines suggest

 ICS/LABA drawbacks
 Which ICS/LABA?
 Which COPD patient will benefit from ICS?

The LABA/ICS combination addresses the multicomponent nature of COPD more than does LABA or ICS treatment alone.
A I R F L O W L I M I T A T I O N
Cazzola M, Dahl R. CHEST 2004; 126:220–237

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

Trough forced expiratory volume in one second (FEV
1
) change from baseline—six-month and 12-month class results.
Cochrane Database Syst Rev. 2014;3, CD010844

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

The FORWARD study: Kaplan-Meier plot of time to first COPD exacerbation
Respir Med. 2014 Aug;108(8):1153-62.
BDP/FOR
FOR
• 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.

When added to LABA in COPD,
ICS reduce exacerbations only in patients with FEV1 ≤ 40%.
Puhan MA, et al. BMC Medicine 2009, 7:2

Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD
Withdrawal of Inhaled Steroids during Optimized
Bronchodilator Management (WISDOM)
N Engl J Med Oct 2, 2014;371:1285-94.

Combination therapy ICS/LABA versus LABA monotherapy

Agenda
 COPD Management
 What guidelines suggest
 ICS/LABA combination therapy

 Which ICS/LABA?
 Which COPD patient will benefit from ICS?

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
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 corticosteroids in COPD and the risk of serious pneumonia
Thorax 2013;68:1029-1036

Relationship between inhaled steroids and
Community-Acquired Pneumonia
Almirall J, et al. PLoS ONE 2013 8(9): e73271.
ICS had no impact on hospitalisation for community-acquired pneumonia, and had no association with ICU admission, days-to-clinical recovery or mortality.

ICS/LABA had the lowest risk of mortality when compared with placebo, tiotropium or LABA only
Thorax 2013 Jan;68(1):48-56

Agenda
 COPD Management
 What guidelines suggest
 ICS/LABA combination therapy
 ICS/LABA drawbacks

 Which COPD patient will benefit from ICS?

Relative effectiveness of budesonide/formoterol and fluticasone propionate/salmeterol
Clin Ther 2010 Jul;32(7):1320-8.
•
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.

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
The efficacy and safety of the novel oncedaily 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

Adverse events of special interest with once-daily fluticasone furoate/vilanterol compared with individual components and placebo in patients with moderate to severe COPD
CS corticosteroid ,
CV cardiovascular ,
FF fluticasone furoate ,
LRTI lower respiratory tract infection ,
PL placebo ,
VI vilanterol ,
ø indicates <1 %
Drugs (2014) 74:1509–1522

Efficacy and safety characteristics of mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination in subjects with moderate to very severe COPD
International Journal of COPD 2012:7 73–86

Because there are insufficient trials of head-to-head comparison design, adequate duration (>12 weeks) or with clinically relevant outcomes, it is currently difficult to recommend any of ICS/LABA combination over another
Curr Respir Care Rep (2014) 3:121–132

Agenda
 COPD Management
 What guidelines suggest
 ICS/LABA combination therapy
 ICS/LABA drawbacks
 Which inhaled corticosteroid?


Moving from the Oslerian paradigm to the postgenomic era: are asthma and COPD outdated terms?
•
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 identify those subjects with COPD with or without a favorable response to ICS
Vanfleteren LEGW, et al. Thorax 2014;69:72–79.

A new approach to grading and treating COPD based on clinical phenotypes
Marc Miravitlles, et al. Prim Care Respir J 2013; 22(1): 117-121
Phenotypes of COPD
• Infrequent exacerbators with either chronic bronchitis or emphysema
•
Overlap COPD-asthma
•
Frequent exacerbators with emphysema predominant
•
Frequent exacerbators with chronic bronchitis predominant

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 use of ICS in COPD, at least in some subtypes of COPD

Cazzola M, et al. Expert Opin. Pharmacother. (2013) 14(18):2489-2499
The question, now, is no longer whether and when to add an ICS in the treatment of COPD patients, but:
• ICSs are really useful in COPD patients without chronic bronchitis?
• Which of the anti-inflammatory treatments available (ICSs or phosphodiesterase 4 inhibitors) are the most effective in subjects with
COPD and chronic bronchitis?
• In frequent exacerbators, long-lasting bronchodilators may prevent exacerbations even in the absence of an ICS?
• In non-frequent exacerbators, what is the utility of combined therapy that include ICS?
The answer to these questions would allow us to optimize the use of ICSs in COPD