COPD Pharmacology Management West Suffolk Integrated Formulary · COPD – Pharmacology Management West Suffolk Integrated Formulary Dr Linda Pearce Respiratory Consultant Nurse West

COPD – Pharmacology Management West Suffolk Integrated Formulary

Dr Linda Pearce Respiratory Consultant Nurse West Suffolk Hospital NHS Foundation Trust

Declaration Linda Pearce has undertaken advisory board meetings, lectures and received support to attend educational meetings from

Astra Zeneca

Boehringer Ingelheim

Chiesi

NAPP

Pfizer

TEVA

Local formulary decision making

Meeting • 4 Respiratory Medical Consultants • 1 Respiratory Nurse Consultant • 2 Specialist nurses • WCCCG med management representative x2 • WSFT - Chief Pharmacist

• Review of Evidence

• Feedback from practice visits • Approval process - WSCCG

Why LAMA and not LABA as monotherapy?

Clinical trials have shown a greater effect on exacerbations rates for LAMA vs LABA treatment

Evidence Reducing exacerbations - level A Hospitalisation – level B Vogelmeier et al. Tiotropium versus salmeterol for prevention of exacerbation of COPD. N Engl J Med 2011;364 (12):1093-103 Decramer et al. Once daily indacaterol vs tiotropium for patients with severe COPD (Invigorate): a randomised blinded, parallel-group study. The Lancet Respiratory medicine 2013;1(7):524-33

Rationale for combining long-acting bronchodilators

Inhaled bronchodilators are the foundation of COPD treatment

Most patients with COPD improve with bronchodilation

Maximal bronchodilation is not achieved using clinically approved doses of one class of bronchodilator alone

There could be synergistic interactions between 2-agonists and anticholinergics

Cazzola M, Molimard M. Pulm Pharmacol Ther 2010;23:257-67

Bronchodilator therapy – GOLD 2017

The SPARK study indicated that Ultibro® was superior in reducing the risk of exacerbations versus long-acting bronchodilator monotherapy

The FLAME study confirmed that Ultibro® reduced the risk of exacerbations to a greater extent than LABA/ICS

The BLAZE study (in patients with moderate to severe COPD) confirmed that Ultibro ® was superior to placebo and tiotropium on patient reported dyspnoea

Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. http://goldcopd.org

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Rationale for FLAME: similar exacerbation rates were observed with SFC and tiotropium in INSPIRE

In INSPIRE, rates of exacerbations requiring antibiotics or systemic corticosteroids at 2 years were similar between tiotropium and SFC treatment groups1

Rat

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f ex

acer

bat

ion

s re

qu

irin

g an

tib

ioti

cs

or

syst

emic

co

rtic

ost

ero

ids

per

yea

r 2.0

1.5

1.0

0.5

0.0

p=0.656 (ns)

Tiotropium 18 μg o.d. (n=665) SFC 50/500 μg b.i.d. (n=658)

1.32 1.28

FLAME2 was designed to evaluate LABA/LAMA versus LABA/ICS in patients with a history of ≥1 exacerbation in the preceding year

INSPIRE = Investigating New Standards for Prophylaxis in Reducing Exacerbations; ns = not significant; SFC = salmeterol/fluticasone propionate

1.Wedzicha JA, et al. Am J Crit Care Med 2008 2. Wedzicha JA, et al. N Engl J Med 2016

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Patients targeted by inclusion criteria

C D

A B

Patient population approximated to GOLD D

Inclusion criteria

•Post-bronchodilator FEV1 ≥25 and <60% of predicted normal

•Symptomatic as defined by mMRC ≥2

•≥1 documented COPD exacerbation requiring treatment with antibiotics and/or systemic corticosteroids within 1 year of randomization

Primary outcome

Rate of all COPD exacerbations (mild/moderate/severe) during 52 weeks of treatment

Primary objective

To demonstrate that IND/GLY was at least non-inferior to SFC

Secondary objective

If non-inferiority could be established, the secondary objective was to demonstrate that IND/GLY is superior to SFC

Wedzicha JA, et al. N Engl J Med 2016

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Ultibro® Breezhaler® significantly reduced the rate of all (mild/moderate/severe) exacerbations versus SFC over 52 weeks

All

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ns (

an

nu

aliz

ed

ra

te)

3.0

4.0

2.0

RR (95% CI) 0.89 (0.83, 0.96), p=0.003

1.0

0

11% reduction

IND/GLY 110/50 μg o.d. (n=1,518)

SFC 50/500 μg b.i.d. (n=1,544)

5.0

Wedzicha JA, et al. N Engl J Med 2016

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The incidence of pneumonia was significantly lower with Ultibro® Breezhaler® than with SFC

Preferred term, n (%)

IND/GLY

110/50 μg o.d.

(n=1,678)

SFC

50/500 μg b.i.d.

(n=1,680)

Patients with at least one AE 1,459 (86.9) 1,498 (89.2)

Adverse events ≥3% in any treatment group

Chronic obstructive pulmonary disease 1,299 (77.4) 1,374 (81.8)

Nasopharyngitis 197 (11.7) 195 (11.6)

Viral upper respiratory tract infection 132 (7.9) 138 (8.2)

Upper respiratory tract infection bacterial 125 (7.4) 168 (10.0)

Lower respiratory tract infection 82 (4.9) 98 (5.8)

Upper respiratory tract infection 81 (4.8) 83 (4.9)

Pneumonia 53 (3.2) 80 (4.8)

Cough 50 (3.0) 51 (3.0)

Dyspnea 49 (2.9) 51 (3.0)

Influenza 35 (2.1) 56 (3.3)

Oral candidiasis 20 (1.2) 71 (4.2)

SAE(s) 308 (18.4) 334 (19.9)

Death 24 (1.4) 24 (1.4)

Discontinuation due to AE(s) 126 (7.5) 143 (8.5)

Discontinuation due to SAE(s) 85 (5.1) 87 (5.2)

Discontinuation due to non-SAE(s) 49 (2.9) 70 (4.2)

Radiographic imaging was required to confirm pneumonia AE = adverse event; SAE = serious adverse event

P=0.02

Wedzicha JA, et al. N Engl J Med 2016

ICS use in COPD/side effects

• Patients more vulnerable to side effects

• Older

• More likely to receive oral prednisolone

• Higher doses ICS used in COPD

• Life use

• Pneumonia

• Increased risk fractures

• Skin bruising/delayed healing

• TB – endemic areas

• Diabetes

• Cataracts

• Dysphonia & candidasis

Inhaled corticosteroids

Regular treatment with ICS increases risk of pneumonia especially in those with severe disease

Evidence level – A

Triple therapy improves lung function, symptoms, health status

Evidence level – A

And reduces exacerbations

Evidence level - B

GOLD 2017

Published Papers

Brusselle et al. The inevitable drift to triple therapy in COPD: an analysis of prescribing pathways in the UK. International Journal of COPD. 2015:10 2207-2217

http://www.dovepress.com.dx.doi.org/10.21.47/COPD.S91694

D’Urzo et al. A re-evaluation of the role of inhaled corticosteroids in the management of patients with chronic obstructive pulmonary disease

Journal Expert Opinion on Pharmacotherapy 2015:16, Issue 12. 1845-1860

http://www.tandfonline.com/doi/full/10.1517/14656566.2015.1067682

COPD - a complex and heterogeneous disease

several different pathophysiological mechanisms

ICS may have an effect on some components of the disease if airway inflammation is present.

COPD phenotypes appear to benefit from ICS

ACO

Frequent exacerbators

Eosinophilia

Inhaled corticosteroids in COPD: the clinical evidence. Ernst P, Saad N, Suissa S.Eur Respir J. 2015 Feb; 45(2):525-37.

Summary of studies evaluating the withdrawal of ICS in patients with COPD

Alan G Kaplan. Applying the wisdom of stepping down inhaled corticosteroids in patients with COPD: a proposed algorithm for clinical practice.

Int J Chron Obstruct Pulmon Dis. 2015; 10: 2535–2548.

Not superior to any other product

Dose equivalence

Pneumonia, fracture risk

Fluticasone furoate/Vilanterol -Relvar

1.Barnes PJ. Chest. 2000; 117 (2 suppl): 10S – 14S 2.Barnes PJ. Am J Respir Crit Care Med. 2000; 161:342-344 3.Keatings VM et al. Am J Respir Crit Care Med. 1997;155: 542-548 4.Culpitt SV et al. Am J Respir Crit Care Med. 1999; 160: 1635 - 1639

COPD Placebo Inhaler device kit

Add own Spacer device

What is on the Horizon?

• More generic and branded generic products

• Triple therapy – ICS, LAMA, LABA