MANAGEMENT OF COPD: WHAT ARE ALL THESE NEW INHALERS?

RIDGE MEADOWS HOSPITAL GRAND ROUNDS

MARCH 13, 2018

STEPHANIE TSANG, INTERNAL MEDICINE AND RESPIROLOGY

CONFLICT OF INTEREST

• HONORARIA FROM ASTRA ZENECA, BOEHRINGER INGELHEIM, GRIFOLS, MERCK

LEARNING OBJECTIVES

AT THE END OF THIS SESSION, PARTICIPANTS WILL BE ABLE TO:

1) ESTABLISH A DIAGNOSIS OF COPD

2) ASSESS FOR SYMPTOMS OF COPD, FREQUENCY OF EXACERBATIONS, AND INTEGRATE THESE FEATURES INTO MANAGEMENT OF COPD

3) UTILIZE THE NEW CANADIAN THORACICS SOCIETY 2017 GUIDELINES IN MANAGEMENT OF COPD

4) EXPLAIN HOW TO USE THE NEW AVAILABLE INHALERS IN THE CANADIAN MARKET

PLEASE NOTE THAT WE WILL NOT BE DISCUSSING MANAGEMENT OF COPD EXACERBATIONS IN THE HOSPITAL SETTING.

CTS GUIDELINES 2008

• WHAT IS COPD?

• COPD, A RESPIRATORY DISORDER LARGELY CAUSED BY SMOKING, IS CHARACTERIZED BY PROGRESSIVE, PARTIALLY REVERSIBLE AIRWAY OBSTRUCTION AND LUNG HYPERINFLATION, SYSTEMIC MANIFESTATIONS, AND INCREASING FREQUENCY AND SEVERITY OF EXACERBATIONS

O’Donnell DE, Hernandez P, Kaplan A, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease –2008 update – highlights for primary care. Can Respir J. 2008;15(Suppl A):1A-8A.

CTS GUIDELINES 2008

• TARGETED FOR SCREENING?

• SMOKERS OR EX-SMOKERS >40 YEARS OLD AND HAS SYMPTOMS OF COUGH, CHRONIC SPUTUM PRODUCTION, DYSPNEA ON EXERTION, WHEEZING, OR FREQUENT COLDS THAT PERSISTS.

O’Donnell DE, Hernandez P, Kaplan A, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease –2008 update – highlights for primary care. Can Respir J. 2008;15(Suppl A):1A-8A.

CTS GUIDELINES 2008

• DIAGNOSIS?• SPIROMETRY SHOWS POST-BRONCHODILATOR FEV1/FVC

GOLD 2006: SPIROMETRY

ESTABLISHED DIAGNOSIS OF COPD WITH BOTH CLINICAL FEATURES AND SPIROMETRY CONFIRMATION….

NOW WHAT??

• LAST COPD GUIDELINES FROM 2007 WITH UPDATE IN 2008

• MANY NEW INHALERS HAVE ENTERED THE MARKET SINCE THEN

Management of Stable COPD

© 2017 Global Initiative for Chronic Obstructive Lung Disease

► Once COPD has been diagnosed, effective management should be based on an individualized assessment to reduce both current symptoms and future risks of exacerbations.

CTS 2017: MANAGEMENT OF COPD

COPD PHARMACOTHERAPY

ASSESS SYMPTOMS

• MRC DYSPNEA SCALE

• CAT = COPD ASSESSMENT TOOL

MEDICAL RESEARCH COUNCIL DYSPNEA SCALE

COPD ASSESSMENT TOOL

• VALIDATED SIMPLE QUESTIONNAIRE

• MEASUREMENT OF HEALTH STATUS

COPD PHARMACOTHERAPY

ASSESS EXACERBATIONS

Follow-up days

205 hospitalized patients, long-term follow-up

8.3% died 1st admission

0.5

0.6

0.7

0.8

0.9

1.0

0 200 400 600 800 1000

Cum

ulat

ive

surv

ival 24%

33%39%

49%

1200

1. Gunen H, et al. Eur Respir J. 2005;26:234-41.2. Suissa S, Dell’Aniello S, Ernst P. Thorax. doi: 10.1136/thorax.jnl-2011-201518.

50% of COPD patients are dead within 4 years of being admitted for first time with COPD2

WHAT IS INFREQUENT VS FREQUENT?

• USE GLOBAL INITIATIVE FOR CHRONIC OBSTRUCTIVE LUNG DISEASE RECOMMENDATIONS

ABCD Assessment Tool

© 2017 Global Initiative for Chronic Obstructive Lung Disease

COPD PHARMACOTHERAPY

LAMA INHALERS FOR COPD IN CANADA

LAMA

DPI HandiHaler/SMI Respimat

Spiriva®§(tiotropium)

DPI Breezhaler Seebri®(glycopyrronium)*

DPI Genuair Tudorza®(aclidinium)*

DPI Ellipta Incruse®(umeclidinium)*

CLASS INHALER NAMEBRAND NAME/GENERIC NAME

Recently approved (since 2012).DPI, dry powder inhaler; SMI, soft mist inhaler.

§ Spiriva® Respimat is also approved for reduction of exacerbations.

These slides have been supplied, on request, by AstraZeneca Scientific Affairs. For complete therapeutic and safety information please consult the respective Product Monograph.

PresenterPresentation NotesDPI, dry powder inhaler; SMI, soft mist inhaler.All LAMAs are approved for maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.Spiriva Respimat is also approved for reduction of exacerbations.

EFFICACY OF LAMA’S IN COPD

Trough FEV1 (L)MCID >= 0.1

SGRQ Total ScoreMCID = -4.0

TDI ScoreMCID >= 1.0

Tiotropium (Spiriva)18 µg qd

0.11 (0.09, 0.13)

-2.45 (-3.18, -1.71)

0.92 (0.71, 1.13)

Glycopyrronium (Seebri)50 µg qd

0.13 (0.09, 0.17)

-3.11 (-4.38, -1.84)

0.92 (0.59, 1.25)

Aclidinium bromide (Tudorza ) 400 µg bid

0.13(0.07, 0.19)

-4.63 (-6.85, -2.42)

1.00 (0.43, 1.57)

Umeclidinium bromide (Incruse) 62.5 µg qd2

0.115-0.3

(-0.8, 0.2)1.00

(0.5, 1.5)

Data are change from baseline vs. placebo (95% CI) at 24 weeks.1. Karabis et al. Int J COPD. 2013;8:405-423; 2. Donohue JF, et al. Resp Med. 2013;107:1538-1546.

These slides have been supplied, on request, by AstraZeneca Scientific Affairs. For complete therapeutic and safety information please consult the respective Product Monograph.

PresenterPresentation NotesSpeaker Notes:Karabis 2013The efficacy of aclidinium was compared with tiotropium and glycopyrronium, using a network meta-analysis (NMA) of randomized controlled trials (RCTs) in moderate-to-severe COPD patients.

Twenty-one studies (22,542 patients) were included: aclidinium 400 μg BID (three studies); tiotropium 5 μg QD (three studies); tiotropium 18 μg QD (13 studies); and glycopyrronium 50 μg QD (two studies).

Regarding trough FEV1 at 24 weeks, aclidinium demonstrated comparable efficacy to tiotropium 5 μg (difference in change from baseline [CFB]), (0.02 L [95% credible interval CrI −0.05, 0.09]); tiotropium 18 μg (0.02 L [95% CrI −0.05, 0.08]); and glycopyrronium (0.00 L [95% CrI −0.07, 0.07]).

Aclidinium resulted in higher improvement in SGRQ score at 24 weeks, compared to tiotropium �5 μg (difference in CFB, −2.44 [95% CrI −4.82, −0.05]); and comparable results to tiotropium 18 μg (−1.80 [95% CrI −4.52, 0.14]) and glycopyrronium (−1.52 [95% CrI −4.08, 1.03]).

Improvements in TDI score were comparable for all treatments.

Maintenance treatment with aclidinium 400 μg BID is expected to produce similar improvements in lung function, health-related quality of life, and dyspnea compared to tiotropium 5 μg QD; tiotropium 18 μg QD; and glycopyrronium 50 μg QD.

Umeclidium has not been compared in a network analysis. Data was taken from a phase III trial.

References:�1. Karabis A, et al. Comparative efficacy of aclidinium versus glycopyrronium and tiotropium, as maintenance treatment of moderate to severe COPD patients: a systematic review and network meta-analysis. Int J COPD. 2013;8:405-423.2. Donohue JF, et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Resp Med. 2013;107:1538-1546.

COMBINATION LABA/LAMA INHALERS FOR COPD IN CANADA

• *APPROVED DEC 2013• **APPROVED MAY 2015• ***APPROVED APRIL 2015

Fixed-dose combination LABA/LAMA

DPI Ellipta Anoro®(vilanterol/umeclidinium)*

DPI Breezhaler Ultibro®(indacaterol/glycopyrronium)*

SMI Respimat Inspiolto®(olodaterol/tiotropium)**

DPI Genuair Duaklir®(formoterol/aclidinium)***

CLASS INHALER NAMEBRAND NAME/ GENERIC NAME

PresenterPresentation NotesDPI, dry powder inhaler.

• IN PATIENTS WITH MODERATE TO SEVERE COPD, LABA/LAMA COMBINATION THERAPY SHOWS IMPROVEMENT OVER PLACEBO AND MONOTHERAPIES IN:

• LUNG FUNCTION (TROUGH FEV1)

• QUALITY-OF-LIFE SCORES (SGRQ)

• SYMPTOM SCORES (TDI)

• EXACERBATION RATES

COMBINATION LABA/LAMA VS. MONOTHERAPIES IN MODERATE TO SEVERE COPD

SAE, serious adverse event; SGRQ, St. George’s Respiratory Questionnaire; TDI, transitional dyspnea index.Oba Y, et al. Thorax 2016;71(1):15-25.

WHEN DO WE USE ICS?

• INSUFFICIENT EVIDENCE IN STABLE COPD TO DETERMINE WHETHER INHALED LAMA + ICS/LABA CONFERS ADDITIONAL BENEFIT TO INHALED LAMA+LABA IN REDUCING SYMPTOMS

• RECOMMEND LAMA + ICS/LABA TO PREVENT AECOPE FOR PATIENTS EXPERIENCING AECOPD DESPITE USE OF INHALED LAMA OR ICS/LABA

• FOR ACO, INITIATE MAINTENANCE THERAPY WITH A ICS/LABA AND CONSIDER STEP UP TO HIGH DOSE, ADDITION OF LAMA, OR BOTH BASED ON SYMPTOMS

NONPHARMACOLOGICAL MANAGEMENT

• SMOKING CESSATION

• VACCINATIONS

• REVIEW INHALER TECHNIQUE!!!

• COPD EDUCATOR/SELF MANAGEMENT

• PULMONARY REHABILITATION

CASE 1

• MR. A: 65M, 30-PACK-YEAR SMOKING HISTORY, PRESENTS WITH PROGRESSIVE SOB, COUGH, AND CHRONIC SPUTUM PRODUCTION. NO PRIOR DIAGNOSIS OF ASTHMA. NO PREVIOUS EXACERBATIONS. NOT ON ANY CHRONIC INHALERS, USES VENTOLIN PRN.

• SPIROMETRY SHOWS FEV1/FVC=0.55, FEV1=65%PREDICTED, FVC 90%PREDICTED. NO SIGNIFICANT BRONCHODILATOR RESPONSE

• SYMPTOMS: MRC 2

• WHAT WOULD YOU CONSIDER FOR MANAGEMENT?

COPD PHARMACOTHERAPY

CASE 2

• MRS. B: 75F PRESENTS TO ER WITH ACUTE SHORTNESS OF BREATH, WHEEZING. 60-PACK-YEAR CURRENT SMOKER. RECENT VIRAL SYMPTOMS. ONLY USES VENTOLIN PRN.

• PREVIOUS SPIROMETRY FROM 2 YEARS AGO: FEV1/FVC=0.55, FEV1=40%PRED, FVC 85%PRED, NO SIGNIFICANT BRONCHODILATOR RESPONSE

• CXR: NO EVIDENCE OF PNEUMONIA

• TREATED IN ER FOR COPD EXACERBATION, IMPROVED AFTER 3 DAYS OF ABX AND PREDNISONE.

• NO PRIOR HISTORY OF EXACERBATION BEFORE THIS PRESENTATION

• WHAT PHARMACOLOGICAL MANAGEMENT WOULD YOU CONSIDER? (NOT ACCORDING TO OUR COPD PATHWAY)

COPD PHARMACOTHERAPY

FLAME – ROLE OF LABA/LAMA?

FLAME – STUDY DESIGN

Double-blind treatment period (52 weeks)

Day –35 to Day –29

Day 1 to Day 365

30-day safety follow-up

Screening period

IND/GLY 110/50 μg q.d.

SFC 50/500 µg b.i.d.

Day –28 to Day –1

Visit 1

Day 366 to Day 395

Visit 101

52-week, multicenter, randomized, double-blind, parallel-group, double-dummy study

Prerandomization period

12 clinic visitsVisit 201

Randomization

Run-in period

PresenterPresentation NotesRun in all patients treated with tiotropium 18ug daily. Discontinued at start of randomization.

Inclusion: Smokers and exsmoker >10-pack year, >40 years old, FEV1 25-60%, at least 1 exacerbation in last year, stable COPD for at least 60 days prior to screening, MMRC 2 at leastExclusion: long QT, blood eos >600, recent exacerbation 6 weeks prior to visit 1

P=0.003

P

33

LABA/LAMA SHOWED SUPERIORITY IN REDUCING ANNUAL RATE OF ALL EXACERBATIONS VS. ICS

3.0

4.0

2.0

1.0

0

5.0

Analysis of the per protocol set (PPS)

All

exac

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tions

(ann

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ed r

ate)

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

11% reduction

SFC 50/500 μg bid(N=1544)

IND/GLY 110/50 μg qd(N=1518)

bid, twice daily; CI, confidence interval; GLY, glycopyrronium; IND, indacaterol; qd, once daily; RR, rate ratio; SFC, salmeterol/fluticasone propionate combination.

Wedzicha JA, et al. N Engl J Med 2016;374:2222-34.

PresenterPresentation NotesThis is the first study to measure the efficacy of a LAMA/LABA versus an ICS/LABA on exacerbations in patients with moderate-to-severe COPD and a history of exacerbations (at least one during the previous year).

ReferenceWedzicha JA, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med 2016;374:2222-34

Chart1

All exacerbationsAll exacerbations

SFC 50/500 μg b.i.d. (N=1,544)

IND/GLY 110/50 μg q.d. (N=1,518)

4.03

3.59

Sheet1

SFC 50/500 μg b.i.d. (N=1,544)IND/GLY 110/50 μg q.d. (N=1,518)

All exacerbations4.033.59

CASE 3

• MR. C, 45M PRESENTS WITH INCREASED COUGH AND SHORTNESS OF BREATH. HISTORY OF ASTHMA AS CHILD, IMPROVED DURING TEENAGE YEARS. HAS 30-PACK-YEAR CURRENT SMOKING HISTORY. HAS HISTORY OF SEASONAL ALLERGIES. CURRENTLY ON VENTOLIN PRN.

• LAST SPIROMETRY: FEV1/FVC 0.50, FEV1=65%PRED, FVC 87%PRED, 20% CHANGE FEV1.

• SYMPTOMS: MRC 3. HAS ~ 1 EPISODE OF “BRONCHITIS” ANNUALLY

• WHAT WOULD YOU CONSIDER FOR MEDICAL MANAGEMENT?

COPD PHARMACOTHERAPY

CASE 4

• MR. D, 80M PRESENTS TO ER WITH COUGH, CXR CONSISTENT WITH PNEUMONIA. KNOWN LONGSTANDING HISTORY OF COPD, 40-PACK-YEAR SMOKING HISTORY. ON TREATMENT WITH ADVAIR DISKUS 500 AND SPIRIVA HANDIHALER FOR MANY YEARS.

• LAST SPIROMETRY FROM 2008: FEV1/FVC 0.55, FEV1 45%PRED, FVC 80%PRED, NO SIGNIFICANT BRONCHODILATOR RESPONSE.

• SYMPTOMS: MRC 3. LAST EXACERBATION ABOUT 3 YEARS AGO, DOES NOT OCCUR FREQUENTLY.

• TREATED IN HOSPITAL FOR PNEUMONIA, CLINICALLY IMPROVED AND READY FOR DISCHARGE

• WOULD YOU MAKE ANY CHANGES TO HIS INHALER THERAPY?

COPD PHARMACOTHERAPY

INCREASED RISK OF PNEUMONIA FIRST IDENTIFIED IN THE TORCH STUDY

0

5

10

15

20

25

0 24 48 72 96 120 144

Time to pneumonia (wks)

Prob

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f pne

umon

ia (%

)

1. Calverley PM, et al. N Engl J Med. 2007;356:775-89; 2. Crim C, et al. Eur Respir J. 2009;34:641-7.

Time to pneumonia in TORCH study (3-y follow-up, n=6112)

PlaceboSalmeterol

Fluticasone

Fluticasone + salmeterol

TORCH = Towards a Revolution in COPD Health trial

PresenterPresentation NotesSpeaker Notes:An issue of potential concern with the use of ICS/LABA combination treatments in COPD patients is an associated increased risk of pneumonia. This association has been observed in several studies and clinical trials and was first identified in the large TORCH trial.The large TOwards a Revolution in COPD Health (TORCH) trial (n=6112), was the first study to suggest a link between inhaled corticosteroids (ICS) and an increase the risk of pneumonia in patients with COPD. This was the first study that was large enough to detect infrequent events like pneumonia. The probability of pneumonia during the 3-year study period was significantly greater among patients in the ICS groups: 19.6% with fluticasone propionate + salmeterol (p

REDUCTIONS IN ALL PNEUMONIAS AND HOSPITALIZED PNEUMONIAS IN THE PATHOS STUDY

ADJUSTED YEARLY PNEUMONIA EVENT RATES COMPARED USING POISSON REGRESSION ANALYSIS.

Fluticasone/salmeterol groupAny pneumoniaHospitalised pneumonia

Budesonide/formoterol groupAny pneumoniaHospitalised pneumonia

Cum

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pneu

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per

100

patie

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All pneumoniasRR 1.73 (1.57; 1.90)P

Bacteria

Fluticasone Fluticasone/GCS-receptor

Fluticasone/salmeterol

Budesonide/formoterol

Mucosa/Lung tissue

Wedzicha JA, et al. AJRCCM. 2008; Calverley PM, et al. Chest. 2011;139:505; Patterson C, et al. Respir Res. 2012;13:40; Ek A, et al. Allergy. 1999;54:691; Miller-Larsson, et al. AJRCCM. 2000;162:145; Johnsson M, et al. Allergy. 1995;50:s11-14; Dalby C, et al. Respir Res. 2009;10:104.

ASL = Airway surface liquid

BudesonideBudesonide/GCS-receptor

ASL

• Local bacteria proliferation occurs during infections• Bacterial colonization increases with disease severity in ~50% of COPD patients

AN IMMUNOSUPPRESSANT / INFECTION HYPOTHESIS

• Absorbed readily (mins)

• Speculated to have less impact on local immune response and bacterial growth

• Remains on mucosa (hours)

• Speculated to suppress local immune response, permitting bacterial growth

PresenterPresentation NotesSpeaker Notes:There are two hypothesis for this observed difference between BUD/FORM and FLU/SALM with respect to pneumonia rates:FLU is 10-fold more immunosuppressive than BUD.1Pharmocokinetic differences between the molecules may lead to BUD having a faster uptake from the airways into the mucosa. BUD is less lipophilic than FLU, dissolving more rapidly in airway mucus and more rapidly absorbed into the airway tissue and systemic circulation. FLU is highly lipophilic/less water soluble and may stay in the airways longer. Because it remains in the airways it is more apt to be expectorated or cleared from the sputum.2 Because FLU remains in the airway lining fluid longer it more potently inhibits cytokine release from lung epithelial cells suppressing the immune response to pneumonia causing bacteria.1,2 BUD takes mins to dissolve in the airway surface liquid and be absorbed, FLU is less water soluble and takes >8 hours to dissolve in the liquid and be absorbed.3

References:Ek A, et al. Fluticasone and budesonide inhibit cytokine release in human lung epithelial cells and alveolar macrophages. Allergy. 1999; 54(7):691-9.Dalby C, et al. The bioavailability and airway clearance of the steroid component of budesonide/formoterol and salmeterol/fluticasone after inhaled administration in patients with COPD and healthy subjects: a randomized controlled trial. Respir Res. 2009;10:104Högger P, et al. Biochemical characterization of a glucocorticoid-induced membrane protein (RM3/1) in human monocytes and its application as model system for ranking glucocorticoid potency. Pharm Res. 1998;15:296-302.

QUESTIONS?

Management of COPD: �What are all these new inhalers?Conflict of InterestLearning ObjectivesCTS Guidelines 2008CTS Guidelines 2008CTS Guidelines 2008GOLD 2006: SpirometryEstablished diagnosis of COPD with both clinical features and spirometry confirmation…. �Now what??Slide Number 9CTS 2017: Management of COPDCOPD PHarmacotherapyAssess SymptomsMedical Research Council Dyspnea ScaleCOPD Assessment ToolCOPD PHarmacotherapyAssess exacerbationsWhat is infrequent vs frequent?Slide Number 18COPD PHarmacotherapyLAMA Inhalers for COPD in CanadaEfficacy of LAMA’s in COPDCombination LABA/LAMA inhalers for �COPD in CanadaSlide Number 23When do we use ICS?Nonpharmacological managementCase 1COPD PHarmacotherapyCase 2COPD PharmacotherapyFLAME – role of LABA/LAMA?FLAME – Study DesignSlide Number 32LABA/LAMA showed superiority in reducing �annual rate of all exacerbations vs. ICSCase 3COPD PharmacotherapyCase 4COPD PharmacotherapyIncreased Risk of Pneumonia First �Identified in the TORCH StudyReductions in All Pneumonias and Hospitalized Pneumonias in the PATHOS StudyAn Immunosuppressant / Infection Hypothesis Questions?