2017 GOLD strategy revision · 2018. 3. 20. · The 2017 GOLD strategy update: Therapeutic options overview Inhaled therapy Reference: Global Strategy for the Diagnosis, Management

2017 GOLD strategy revision

ZINC Code: NOR/CPD/0008/17Prepared February 2017

Lill Lena Nyberg

Thomas Jürgens

Medical Department GSK Norway

Section 1: COPD diagnosis and assessment

Evolution of Diagnose and Assessment of COPD:

Reference: 1. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) 2001. 3

Assessment of severity of airflow

obstruction

Spirometry

2001

Stage FEV1 predicted0 At Risk Chronic Symptoms;

Normal SpirometryI Mild COPD < 80%

IIA Moderate COPD 50% - 80%

IIB Moderate COPD 30% - 50%

III Severe COPD< 30%

“For educational reasons, a simple classification of disease severity into four stages is recommended.

The management of COPD is largely symptom-driven, and there is only an imperfect relationship between the degree of airflow-limitation and the presence of symptoms.

The staging, therefore, is a pragmatic approach aimed at practical implementation and should only be regarded as an educational tool, and a very general indication of the approach to management.”

Evolution of Diagnose and Assesment of COPD:

Reference: Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) 2011. 4

Assessment of severity of airflow

obstruction

Spirometry

Assessment of respiratory symptoms

• CAT• mMRC

Assessment of exacerbation risk

Clinical history

2011

CAT: COPD Assessment TestmMRC: Modified Medical Research Council

Impact on the COPD Assessment

5

Lung function Exacerbations in previous year

Symptoms

1% 40%

10% 49%

Reference: Vestbo J, Vogelmeier C, Small M, Higgins V. Understanding the GOLD 2011 Strategy as applied to a real-world COPD population. Respir Med. 2014;108(5):729-36.

Grade FEV1(%

predicted)4 < 30%

3 30–49%2 50–79%

1 >80%

≥ 2

≤ 1

CAT, mMRC

18%

28%

The 2017 GOLD strategy: COPD diagnosis and assessment

6

Grade FEV1(% predicted)

1 ≥80%

2 50–79%

3 30–49%

4 <30%

Assessment of airflow limitation

CAT, COPD Assessment Test; CCQ, Clinical COPD Questionnaire; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; mMRC, Modified Medical Research CouncilReference: 1. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) 2017.

CAT ≥10mMRC ≥2

CAT <10mMRC 0–1

Exacerbation History

≥2 or≥1 leading tohospitalisation

0 or 1 (not leading to hospitalisation)

Assessment of symptoms/risk of

exacerbations

Symptoms

FEV1/FVC <0.7

Spirometrically confirmed diagnosis

Sym

ptom

s an

d/or

risk

fact

ors

© 2017 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner.

Section 2: Therapeutic options overview

• Smoking cessation• Lung rehabilitation• Individualized pharmacologic treatment • Patients are likely to have comorbidities that may add to

their symptomatology and impact their prognosis, and these possibilities should be investigated

The 2017 GOLD strategy update: Therapeutic options overview

General principles

8Reference: 1. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) 2017.

The 2017 GOLD strategy update: Therapeutic options overviewInhaled therapy

9Reference: Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) 2017.

• LABA – Long Acting Beta-2 Agonist• LAMA – Long Acting Muscarinic Antagonist• ICS – Inhaled CorticoSteroids (Not used as monotherapy for COPD)

• Combinations:– ICS/LABA– LAMA/LABA– Triple Therapy (LAMA+ICS+LABA)

The 2017 GOLD strategy update: Therapeutic options overviewInhaled therapy


Patient response, preference and ability to use various drug delivery devices

• About 2/3 of patients do at least make at least 1 error when using their inhalation device

• Main determinants for errors are• Older age• Use of multiple devices• Lack of education for correct inhaler use

• Poor inhaler use leads to poor symptom control

GOLD 2017 Pharmacologicalmanagement

11

Fortsetzen, Stoppenoder Versuch einer anderen

Bronchodilatator-Klasse

LAMA + LABA LABA + ICS

LAMA

Bestehende Symptome

A single bronchodilator (LABA or LAMA)

LAMA + LABA BA

C

Persisting symptoms

Further exacerbation(s)

One Bronchodilatator

Assess benefit

Preferred route

LAMA + LABA LABA + ICSLAMA

LAMA + LABA + ICS

Considermacrolide

Consider roflumilastif FEV1<50% and

patient has chronicbronchitis D

Persistingsymptoms/furtherexacerbation(s)Further

exacerbation(s)


Continue, stop or tryalternative bronchodilator) A

Reference: Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) 2017.

© 2017 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner.

Section 3: GOLD B

Patients with symptoms, no or few exacerbationsPharmacological management Group B

13

LABA LAMA

LAMA/LABA


mMRC breathlessness scores in patients receiving monotherapy with a single long‐acting bronchodilator

45

40

35

30

25

20

15

10

5

00 1 2 3 4

mMRC dyspnoea scores

% o

f sub

ject

s <50%≥50%

Post bronchodilator FEV1 % predicted

56 primary care and specialty centres in the USA in 689 patients (76% tiotropium and 24% LABA)

Adapted from: Dransfield MT et al. Prim Care Respir J. 2011;20:46-53

>50%of patients walkslower than people of the same age or have to stop

Primary endpoint: Trough FEV1 at Day 169: UMEC/VI vstiotropium in moderate to very severe COPD patients(double-blind, double-dummy study†)

Adapted from: 1Maleki-Yazdi M et al. Respir Med 2014; 108:1752–1760; 2Decramer et al. Lancet Resp Med 2014;2 472-4486

ZEP1171151 DB21133602DB21133742∆ Trough

FEV1

*Not statistically significant due to hierarchical testing.

†Patients may not have beenblind to tiotropium

These studies were a 24-week, Phase III, multicenter, randomised, blinded,double-dummy, parallel-group study of UMEC/VI (62.5/25 mcg) versus tiotropium (18 mcg) in patients with moderate-to-very severe COPD

These data are not comparative,correspond to different studies

Umeclidininium/vilanterol Ellipta vstiotropium Handihaler

UMEC/VI 55/22mcg

Mortality FEHR (95 % CrI)

Total SAEs FEHR (95 % CrI)

Cardiac SAEs REHR (95 % CrI)

Dropouts due to AE REHR (95 % CrI)

No. of studies 15 20 16 16

No. of patients 24 041 27 172 25 913 23 529

vs. placebo 1.95 (0.73, 7.71) 1.10 (0.89, 1.38) 1.65 (0.81, 3.35) 0.95 (0.71, 1.28)

vs. LABA 0.99 (0.61, 1.66) 0.96 (0.84, 1.10) 0.82 (0.46, 1.35) 0.92 (0.72, 1.19)

vs. LAMA 0.87 (0.64, 1.16) 1.04 (0.95, 1.14) 0.87 (0.59, 1.27) 1.03 (0.84, 1.26)

16

AE, Adverse Event; CrI, Credible Interval; FE, Fixed-Effects; LABA, Long-Acting beta-agonist; LAMA, Long-Acting muscarinc antagonist; RE, Random Effects; SAE, Serious Adverse Event

Summary effects of LABA/LAMA combinations versus comparators on adverse events

The Dual LAMA/LABA Class Safety Profile is Similar to Monotherapy An integrated network meta-analysis of 20 randomised controlled trials (n=23529 to 27172)

Oba Y, et al. Thorax 2015;0:1–11. doi:10.1136/thoraxjnl-2014-206732

Section 4: GOLD D

GOLD 2017: Group D (inhaled therapy)

LAMA+LABA LABA + ICSLAMA

LAMA + LABA + ICS

Persisting symptoms/further exacerbation(s)


GOLD: “Lack of direct evidence supporting the therapeutic recommendations for patients in groups C and D”




LAMA + LABA + ICS



2 Cochrane reviews2,3:

~25% reduction of exacerbation risk with

• Salmeterol/Fluticasonpropionat• Formeterol/Budesonide

1. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) 2017.

2. Nannini LJ, Poole P, Milan SJ et al.. Combined corticosteroid and long-acting B-agonist in one inhaler vs placebo for COPD (Review). Cochrane. 2013.

3. Nannini lJ, Lasserson TJ, Poole P Combined corticosteroid and long-acting B-agonist in one inhaler vs LABA for COPD (Review). Cochrane 2012

Risk of pneumonia must be balanced againstthe benefit of exacerbation reductionOn-treatment pneumonia & exacerbation rates for Relvar® Ellipta® vs. vilanterol*

VI, vilanterol

0 28 56 84 140 168 224

0

100

200

300

500

600

Num

ber o

f Eve

nts

Days

700

800

400

112 196 280252 336203 364

VI 22 Exacerbation (N=741 events)

Relvar Ellipta Exacerbation (N=554 events) 187 events

Relvar Ellipta Pneumonia (N=58 events)

VI 22 Pneumonia (N=28 events)

30 events

Pooled analysis of two replicate, double‐blind, parallel‐group, one‐year studies comparing Relvar® Ellipta® to Vilanterol 25 mcg in COPD patients with FEV1 <70% predicted and a documented history of >1 moderate /severe disease exacerbations in the preceding year. The 2

studies randomized 1622 & 1633 patients respectively. * Vilanterol is currently not licensed for use.

Adapted from: Dransfield MT., Bourbeau J, Jones PW, et al. Lancet Respir Med 2013;1:210–23. FEV1, forced expiratory volume in 1 second; FF, fluticasone furoate; VI, vilanterol



LAMA + LABA + ICS



~17% reduction of exacerbation risk for

Tiotropium (10 studies, 12.163 patients)2


2. Cooper CB, Anzueto A., Decramer M, et al Int J Chron Obstruct Pulmon Dis 2011; 6: 269-752.

2 Cochrane reviews:~25% reduction of exacerbation risk with

• Salmeterol/Fluticasonpropiont• Formeterol/Budesonide



LAMA + LABA + ICS




2. Wedzicha JA, Decramer M, Ficker JH, et al. Lancet Respiratory Medicine 2013, May;1(3):199-209

SPARK-study

Moderate and severe excacerbartions reduction:

Glycopyrronium/Indacterol vs Glycopyrronium0·88 (0·77–0·99; 0·038)

Glycopyrronium/Indacterol vs Tiotropium0·90 (0·79–1·02; 0·096)



LAMA + LABA + ICS




FLAME-study

Flame study: comparison of indacaterol/ glycopyrronium(QVA149) and SFC 50/500

Wedzicha JA., Banerji D, Chapman KR, et al. N Engl J Med 2016;374:2222-34. DOI: 10.1056/NEJMoa1516385 (online supplement)

Reduction in moderate-severe to severe exacerbations

Trough FEV1 (L)

LS mean

Trough FEV1: indacaterol 150 µg, placebo and salmeterol (all double-blind) after 26 weeks treatment

†††

***

***†††

***p<0.001 vs placebo; †††p<0.001 vs salmeterol Data are least squares means – adjusted for baseline covartiates

Indacaterol 150 µg o.d.Salmeterol 50 µg b.i.d. Placebo

Kornmann O, Dahl R, Centanni S, et al. Eur Respir J 2011;37:273-9

1.2

1.3

1.4

1.5



LAMA + LABA + ICS



4 Trials – Posthoc data for 3 months2 for

Vilanterol/Fluticasonefuorat/Placebovs.Vilanterol/Fluticasonfuorat/Umeclidinium

60% chance of greater clinical response (SGRQ)


2. Siler TM et al Pulm Ther (2016), DOI 10.1007/s41030-016-0012-4 , in press


27

LAMA + LABA LABA + ICSLAMA

LAMA + LABA + ICS



No evidence yet for the benefit of adding ICS to dual bronchodilator



28


LAMA + LABA + ICS



ICS step-down/withdrawal


1,59 1,53

1,141,051,1 1,06

0,90,7

0

0,5

1

1,5

2

2,5

Anzueto et al. 2009(n=797)¹

Ferguson et al. 2008(n=782)²

HZC102970 (n=812)³ HZC102871 (n=812)³

LABA

Mea

n an

nual

rate

ICS withdrawal can increase exacerbation risk*

Annual rate moderate/severe copd exacerbations**

Indirect study comparison

1. Anzueto A et al. Journal of COPD 2009; 6: 320-329. 2. Ferguson GT et al. Respir Med. 2008; 102: 1099-1108. 3. Study HZC102970 and HZC102871: Relvar SmPC (24 June.2016)

These data are not comparative, correspond to different studies

* ICS withdrawal defined as the removal of ICS at randomisation.** Exacerbation rate was the primary endpoint in all of these GSK-sponsored trials.Study ref 1 and 2: propionate/salmeterol (250/50 μg) or salmeterol (50 μg) Studies ref 3: fluticasone furoate/vilanterol (100/25 μg) or vilanterol (25 μg)

Wisdom – subgroup analysisNon-inferiority was declared if the confidence limits did not include 1.20 (< 20% increased risk)

All patients Primary analysis

Adapted from Magnussen H, Disse B, Rodrigues-Roisn R, et al. N Engl J Med 2014;371:1285-94.

0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5

0.94 1.06 1.19

Higher exacerbations (≥2)

Few exacerbations

No ICS

ICS pre-study

NON-INFERIOR LIMIT

30

ICS Withdrawal Better

ICS Continuation Better

Key learnings

1. Spirometry results fail to correlate both with symptoms and exacerbation risk of the individual patient. It should therefore not be used to guide pharmacological treatment of patients

2. Smoking cessation and Lung rehabilitation programs are highly effective interventions3. Correct inhaler use is essential for the treatment. However 2/3 of the COPD patients do

not accomplish this and make at least 1 critical error4. At least 50% of patients remain breathless when treated with LAMA or LABA alone5. Symptoms can be further reduced by combining LAMA and LABA without adding

additional toxicity 6. As of today there is limited direct evidence to support the GOLD C and D

recommendations, except for ICS/LABA and LAMA7. The available evidence for the safe removal of ICS is inconclusive


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2017 GOLD strategy revision · 2018. 3. 20. · The 2017 GOLD strategy update: Therapeutic options overview Inhaled therapy Reference: Global Strategy for the Diagnosis, Management