4/26/2016

Michael D. Skokan MD Pulmonary, Critical Care and Interventional Bronchoscopy The Oregon Clinic Medical Director, Providence Lung Cancer Screening Program

No-nonsense COPD Therapy

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No-nonsense COPD Therapy: Objectives

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 Importance: why you need to know.  Definitions and staging.  COPD vs. asthma vs. asthma-COPD overlap syndrome (ACOS).  Therapy: bronchodilators, inhaled corticosteroids, combination inhalers, azithromycin, daliresp, valves.  Approach to office work-up.  Patient not improving with therapy.

Special Thanks 

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COPD Mortality Rate Increasing 

Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998 3.0 2.5

Coronary Heart Disease

Stroke

Other CVD

COPD

2.0

All Other Causes

1980-2000 13% increase men 187% increase women

1.5 1.0 0.5 0

–59%

–64%

–35%

1965 - 1998 1965 - 1998 1965 - 1998

+163%

–7%

1965 - 1998 1965 - 1998

www.goldcopd.com

COPD: Scope and Etiology 1.1 billion smokers worldwide, increasing to 1.6 billion by 2025 COPD third in cause death

* fourth leading cause of death •1.5 million ER visits •725,000 hospitalizations * 119, 000 deaths •annual cost of $60 billion

•54-70% direct costs due to hospitalizations

Am J Respir Crit Care Med 189:634-9,2014

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COPD Therapy: Explosion of New Drugs

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 Long Acting Anticholinergics/LAMA  umeclidinium 1 puff QD (Incruse)  aclidinium 1 puff BID (Tudorza)

 Long Acting Beta Agonists  olodaterol 2 puffs QD (Striverdi respirmat)  Indacterol 1 puff QD (Arcapta)  Vilanterol 1 puff QD

 Combined LABA/LAMA  vilanterol/umeclidinium 1 puff QD (Anoro)  Olodaterol/tiotropium 2 puffs QD (Stiolto)

 Combined LABA/ICS vilanterol/fluticasonefuorate 1 puff QD (Breo)

Penalizing Hospitals for COPD Readmissions: Medicare Hospital Readmission Reduction Program

  ACA - hospital payments reduced as a penalty for readmission within 30 days of an index hospitalization for COPD starting 10/2014  2013 – for CHF, MI, pneumonia  2, 000 hospitals penalized $280 million  22.6% COPD patients readmitted within 30 days

 Improve quality and reduce cost by financial incentives  May lead to unintended consequences  readmit 22% higher for lower income  safety net and large hospitals higher penalty

Am J Respir Crit Care Med 189: 634-9, 2014

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COPD Definitions   “Chronic obstructive pulmonary disease, a common preventable and treatable disease, is characterized by airflow limitation that is usually progressive and associated the an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and co-morbities contribute to the severity in individual patients.”

COPD vs. Asthma 

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Asthma-COPD Overlap Syndrome (ACOS) NEJM 2015; 373:1241-9

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 Recently, the Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease issued a joint document describing ACOS.  Syndrome is estimated to be present in 15-45% of population with obstructive lung disease.  Not studied: studies of COPD have excluded nonsmokers and asthma studies excluded smokers.  Hallmark is progressive airway obstruction and bronchial hyperresponsiveness.

COPD Standard of Care - 2015

Global Initiative  for Chronic Obstructive L ung Disease www.goldcopd.com

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GOLD Guideline Changes 2013   Change in staging 1-4 to A-D  assess symptoms  mMRC dyspnea scale  COPD Assessment Test (CAT)

 determine frequency of exacerbations  >1 in previous year  FEV1 < 50% (prior GOLD Stage 3 and 4

 MMRC Dyspnea Scale  score range 0-4  increased grade score > 1

 COPD Assessment Test  score range 0-40 (8 questions each 0-5 points)  Increased grade > 9

COPD Assessment Test 

Question Scale 0-5 ( 0 and 5 listed)

Score (0-40)

I never cough – I cough all the time

0-5

I have no phlegm – My chest is completely full of phlegm

0-5

My chest does not feel tight – My chest feels very tight

0-5

Not SOB walking up a hill or 1 flight – very breathless walking up a hill or 1 flight

0-5

Not limited daily activities – very limited daily activities

0-5

Confident leaving my house despite COPD – not confident leaving my house due to COPD

0-5

I sleep soundly – I don’t sleep soundly due to COPD

0-5

I have lots of energy – I have no energy at all

0-5

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mMRC Dyspnea Scale 

mMRC Grade

Description

0

SOB with strenuous exercise

1

SOB when hurrying on level ground or going up a slight hill

2

On level ground walking slower than others or stopping due to SOB walking at your own pace

3

Stop for SOB after walking on level ground 328 ft (100m) or after a few minutes

4

SOB with dressing or to SOB to leave the house

COPD Stage and Therapy

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Prediction Clinical Course COPD with New  Classification  6628 patients with COPD  both systems predict mortality  mortality higher with worse FEV1  mortality worse with symptoms > flares

 new system better predictor exacerbations  disease progresses over time  increased exacerbations  increased hospitalization Am J Respir Crit Care Med 186:975-981, 2012

COPD: Office Approach   History: time course; exposures; tobacco; FH (alpha1-antitrypsin) ; weight loss. Hospitalizations.  Physical exam: wheezes; crackles/murmur; clubbing; obesity.  Tobacco: pack-years; quit attempts (how?); time to first cigarette.  Oxygenation: pulse oximetry with rest and with ambulation); ABG? (polycythemia or obesity).  Labs: hematocrit; bicarbonate.  Spirometry: right diagnosis? severity.

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COPD and Tobacco: NIH Lung Health Study FEV1 % Predicted

82 81 80 79 78 77 76 75 74 73 72

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Quitters Smokers n = 5887 P < 0.05

BL

1

2

3

4

5

Follow-up Years JAMA 272: 1497-1505, 1994

COPD and Tobacco: 

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Patient Group

COPD Therapy  First Choice Therapy

Alternative Therapy

Other Possible Therapies

A

SABA or SAMA PRN

LAMA or LABA; SAMA + SABA

theophylline

B

LAMA or LABA

LAMA + LABA

SABA and/or SAMA; theo

LAMA + LABA +/- ICS

LAMA+LABA LABA/ICS

SABA and/or SAMA; theo

LAMA + LABA + ICS

LAMA + LABA + ICS; PDE-4; azithro

SABA and/or SAMA; theo

C

D

COPD Therapy: Long-acting Beta agonist (LABA)

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 Multiple studies have demonstrated benefit of LABA in stable COPD.  TORCH: 6112 pts with moderate/severe COPD showed decreased exacerbation rates, improved lung function and improved quality of life. No increase in mortality suggesting safety.  Risk of arrhythmia and LABAs examined retrospecively in 76K pts; arrhythma increased (RR 1.27); but lost significance when those with heart disease excluded.  Similar benefit from indacaterol and olodaterol.

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LABA vs. Long-Acting Muscarinic Antagonist (LAMA)

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 Cochrane (2012): Included 7 trials (>12K pts) comparing tiotropium with salmeteroll, formoterol or indacaterol. No difference in QOL, overall hospitalizations or mortality. Spiriva more effective at reducing exacerbations (OR 0.86).  POET trial (NEJM 2011) compared tiotropium to salmeterol in 7376 pts with moderate to severe COPD. Tiotropium better at preventing exacerbations.

Tiotropium vs Salmeterol: POET Trial Prevention of Exacerbations

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 1 year randomized prospective  no control group because both agents vs placebo prevent exacerbations  exacerbations defined  moderate antibiotics and /or corticosteroids  severe hospitalization

 7376 patients: 3707- tio, 3669- salmeterol  64 deaths (1.7%) in tiotropium and 78 deaths (2.1%) in salmeterol group (p = NS)

N Engl J Med 364:1093-1103,2011

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Baseline Charcteristics  tiotropium

salmeterol

Age

62.9 + 9

62.8 + 9

FEV1

1.4 + .5

1.4 + .5

FEV1 % predicted

49 + 13

49 + 13

FEV1/FVC

53 + 11

52 + 12

ICS %

54

53

Oral steroids

2.4

2.3

methylxanthines

23

21

Gold Stage II vs 4

48 vs 9

50 vs 8

Tiotropium Superior to Salmeterol: Preventing Exacerbations

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Annual Rate

% Reduction (p < 0.05)

Moderate exacerbation

7

Severe exacerbation

27

Systemic corticosteroids

18

Antibiotics + corticosteroids

20

36.5 % of patients had an exacerbation no difference in cardiac events

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Combined Therapy for Stable COPD: LAMA +LABA

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Farne HA. Cochrane Database 2015

 Review and meta-analysis of 10 trials (>10K pts) found better QOL; small increase in FEV1 with combo (compared to LAMA alone); adding tiotropium to LABA reduced exacerbations.  No difference noted in other endpoints including mortality, symptoms, SAEs or hospital admissions.

Inhaled Corticosteroids in COPD

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 Data suggests that ICS may decrease exacerbations but have little impact on lung function and mortality.  If used should be used in combination with longacting bronchodilator.  Used with bronchodilator in pts with GOLD stage 3-4 who have significant symptoms and exacerbations.  In TORCH: salmeterol + fluticisone improved secondary end-points of lung function and exacerbations; but minimally decreased mortality compared to placebo.

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LABA/LAMA vs. LABA/LAMA/ICS NEJM 2014;371:1285-94.

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 WISDOM (Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management) was randomized controlled noninferiority trial.  2488 pts with severe/very severe COPD and >/=1 exacerbation in last year; given 6 weeks of tiotropium, salmeterol and fluticisone.  Steroid withdrawal group weaned of steroids by week 12.  Primary endpoint was exacerbations.  ICS withdrawal was noninferior to continuing ICS.

INSPIRE: Study Design

Investigating New Standards for Prophylaxis Inparallel-group, Reducing Exacerbations Randomized, double-blind, double-dummy, multicenter ADVAIR DISKUS 500/50♦ BID (n=658)

Follow-up Period

Run-in

Tiotropium 18 mcg QD HandiHaler® (n=665)

Week

–2 Screen

0

2

8

20

32

44 56 68

Treatment Period

80

92 104 106 End of Treatment

Run-in: Discontinue current COPD meds; Key Inclusion Criteria: prednisolone 30 mg/day + salmeterol 50 mcg BID • 40-80 years of age (mean 65) • ≥10 pack-year history of smoking (mean 40 years) • Post-bronchodilator FEV1