David Young, Pharm.D. Professor of Pharmacotherapy (Clinical) University of Utah Asthma Center Pharmacist dyoung@pharm.utah.edu

Differentiate between the various stages of COPD according to the current GOLD guidelines

Review the current therapeutic options to treat patients with COPD

Formulate a stepwise approach to the treatment of a patient with COPD

Discuss the importance of correct inhaler technique

1) http://www.lung.org/lung-disease/copd/resources/facts-figures/COPD-Fact-Sheet.html Accessed 9/15

12.7 million in US diagnosed in 2011 Estimated 24 million affected Morbidity & Mortality Third most common cause of death in US in 2010 ▪ 134,676 deaths ▪ 715,000 hospitalizations (2010)

Females deaths (70,000)> Males (64,000) in 2010 Cost of COPD in U.S. was ~$50 billion in 2010 1 DEATH EVERY 4 MINUTES

MMWR,2002;5(6):1-16

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

0

0.5

1.0

1.5

2.0

2.5

3.0

1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 –59% –64% –35% +163% –7%

Coronary Heart

Disease

Stroke Other CVD COPD All Other Causes

$29.5 billion (direct) Hospital visits

$8 billion (morbidity) Loss of work

$12.4 billion (mortality) $49.9 BILLION TOTAL COSTS IN 2010

1) http://www.lung.org/lung-disease/copd/resources/facts-figures/COPD-Fact-Sheet.html Accessed 9/15

AIRFLOW LIMITATION

Luminal Plugs

Decrease in Elastic Recoil

Increased Airway Resistance

Airway Inflammation and Fibrosis

A common preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and

associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases.”

GOLD 2015; ACCP

1. Chronic dyspnea ▪ Progressive ▪ Persistent ▪ Worse with exercise

2. Chronic cough ▪ May be intermittent at first ▪ May be unproductive

3. Chronic sputum production ▪ May vary from day to day

Severe COPD: • Fatigue • Weight loss • Cough syncope • Depression • Anxiety

GOLD 2015

COPD = Post-bronchodilator FEV1/FVC < 0.70

GOLD 2015

Severity of Airflow Limitation Based on Post-Bronchodilator FEV1 (Only for patients with FEV1/FVC <0.70)

GOLD 1 Mild FEV1 ≥ 80% predicted

GOLD 2 Moderate 50% ≤ FEV1 < 80% predicted

GOLD 3 Severe 30% ≤ FEV1 < 50% predicted

GOLD 4 Very Severe FEV1 < 30% predicted

GOLD 2015

C D

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OLD

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mMRC 0-1 mMRC >2 CAT <10 CAT >10

Symptoms

Modified Medical Research Council (mMRC) Dyspnea Scale

mMRC Grade Description

0 I only get breathless with strenuous exercise.

1 I get short of breath when hurrying on the level or walking up a slight hill.

2 I walk slower than people of the same age on the level because of breathlessness, or I have to stop for breath when walking on my own pace on the level.

3 I stop for breath after walking about 100 meters or after a few minutes on the level.

4 I am too breathless to leave the house or I am breathless when dressing or undressing.

GOLD 2015

COPD Assessment Test (CAT)

C D

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GOLD 2015

mMRC 0-1 mMRC >2 CAT <10 CAT >10

Symptoms

SMOKING Occupation Indoor & outdoor pollution Genetic Alpha-1-antitrypsin deficiency

Infection Socioeconomic status

Reduce progression of airflow obstruction

Relieve symptoms Improve exercise tolerance Improve health status Prevent and treat exacerbation’s Reduce mortality

GOLD 2015

Patient Group Essential Recommended Local Guidelines

A Smoking cessation

Physical activity

Flu & Pneumococcal Vaccine

B-D Smoking cessation, Pulmonary rehab

Physical activity

Flu & Pneumococcal Vaccine

GOLD 2015

>18yrs currently smoking (2013)

17.8% of all adults (42.1 million people) ▪ 20.5% of males, 15.3% of females

<18yrs (2013)

>3200 smoke 1st cigarette

~2100 occasional smokers become daily smokers

>250,000 middle school and high school students never smoked regular cigarettes but had used e-cigarettes three times as many as 2011

2011

Nearly 7 in 10 (68.9%) adult cigarette smokers wanted to stop smoking.

More than 4 in 10 (42.7%) adult cigarette smokers had made a quit attempt in the past year.

http://www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts/index.htm#use

http://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm

> 18yrs who currently smoke cigarettes was 11.8% in 2011 (1st in US)

>18yr who currently use smokeless tobacco was 3.0% in 2011 (14th in US)

Grades 9–12 who currently smoke cigarettes was 5.9% in 2011 (1st in US)

Grades 9-12 who currently use smokeless tobacco was 3.7% in 2011 (2nd is US)

http://www.cdc.gov/tobacco/data_statistics/state_data/state_highlights/2012/states/utah/index.htm

Graph by Boehringer Ingelheim Pharmaceuticals, Inc. which was adapted from Fletcher CM, Peto R: The natural history of chronic airflow obstruction. Brit Med J 1977; 1:1645-1648.

Nicotine gum(Nicorette 2,4mg) Nicotine patch(Nicoderm 7,14,21mg) Nicotine inhaler (Nicotrol inhaler 10mg) Nicotine nasal spray (Nicotrol NS 0.5mg) Nicotine lozenge (Committ 2mg, 4mg) Bupropion SR (Zyban 150mg) Varenicline (Chantix 0.5mg,1mg)

Patient group

First choice Second choice Alternative

A SAMA prn or SABA prn LAMA or LABA or SABA + SAMA

Theophylline

B LAMA or LABA LAMA + LABA SABA +/-SAMA

C ICS+LABA or LAMA LAMA + LABA PDE-4 inhibitor; SABA +/-SAMA; Theophylline

D ICS+LABA and/or LAMA ICS+LAMA; ICS+LABA+LAMA; LAMA + LABA; LAMA + PDE-4 inhibitor

Carbocysteine; SABA +/-SAMA; Theophylline

GOLD 2014

Ipratropium (Atrovent HFA®, Ipratropium 0.02% neb soln)

Dosage MDI 2 puffs qid Neb soln 500mcg tid-qid

Adverse effects Dry mouth

Tiotropium bromide (Spiriva Handihaler® or Respimat ®) M-3 receptor blocker

1 puff (18mcg) daily (Handihaler® ) or 2 puff (5mcg) daily

Adverse effects Dry mouth, URI, pharyngitis, sinusitis

Additive AE’s with SAMA or LAMA

Singh S, et al. BMJ 2011 Meta-analysis of randomized-controlled

trials ▪ 5 RCT included ▪ RR 1.52 (95% CI, 1.06-2.16) of mortality

Wise RA, et al. NEJM 2013 RDBPC Tiotropium Respimat® (2.5, 5mcg) vs

Handihaler® (18mcg) n=17,135 mean follow-up 2.3 years Risk of Death HR 0.96 (95% CI, 0.84 to 1.09) Non-superior with respect to risk of 1st exacerbation

0.98 (95% CI, 0.87 to 1.14)

Tashkin DP, et al. Respiratory Research 2015 Post-hoc analysis Tiotropium Handihaler® (18mcg) vs

placebo of UPLIFT trial ▪ n=5993 over 4 years ▪ Patients excluded if recent MI (<6 months), any unstable or life

threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or hospitalization for CIII or CIV heart failure w/in 1yr

Post-hoc analysis selected pts who experienced cardiac event during treatment that did not withdraw from trial after 1st event.

N=400 (203 tiotropium vs 197 placebo) Not at increased risk of all-cause mortality or cardiac adverse

events (arrhythmia, MI, CHF)

Aclidinium (Tudorza pressair®) M-3 receptor blocker

1 puff (400mcg) twice daily Adverse effects Headache, pharyngitis, sinusitis

Additive AE’s with SAMA or LAMA

Umeclidinium (Incruse Ellipta®) M-3 receptor blocker

1 puff (62.5mcg) daily Adverse effects Pharyngitis,URTI,Cough

Additive AE’s with SAMA or LAMA

Glycopyrrolate (Seebri Neohaler®) M3 receptor blocker

1 puff (15.6mcg) twice daily Adverse effects Nasopharyngitis,URTI

Products Albuterol

▪ MDI (Albuterol HFA, Proventil HFA, Ventolin HFA, ProAir HFA, Proair Respiclick)

▪ Nebulized (Accuneb, Proventil) ▪ Oral tablets & syrup (Proventil, Proventil Repetab, VoSpire ER)

Levalbuterol ▪ MDI (Xopenex HFA) ▪ Nebulized (Xopenex)

Epinephrine (Asthmanefrine) ▪ Approved >4yrs ▪ 0.5ml (11.25mg epinephrine) via EZ Breathe Atomizer 1-3

inhalations every 3 hours prn (maximum 12 inhalations/24hr ) ▪ Seek medical help if no relief in 20 minutes

Aformoterol (Brovana®) 15mcg neb BID Formoterol (Foradil Aerolizer®) 12mcg puff BID;

(Perforomist®) 20mcg neb BID Indacaterol (Arcapta neohaler®) 75mcg dpi once

daily Olodaterol (Striverdi Respimat®) 2 puffs (5mcg)

daily Salmeterol (Serevent Diskus®) 1 puff (50mcg) BID

LABA + ICS

Medication Device Dose Frequency

Advair Diskus® (fluticasone/salmeterol) DPI 250/50, 500/50 mcg 1 INH BID

Symbicort® (budesonide/formoterol) MDI 160/4.5 mcg 2 INH BID

Breo Ellipta® (fluticasone furoate/vilanterol) DPI 100/25 mcg 1 INH daily

GOLD 2015; Lexi-Drugs

Double-blind, randomized, placebo controlled, multi-center study

N=6184 2 week run-in 3 year treatment period (all taken twice daily) Placebo 50mcg SALM 500mcg FP (high dose) 500mcg FP (high dose)+ SALM 50mcg

Results (FP/SALM vs placebo) Risk of death (HR=0.825, 95% CI=0.681 to 1.002; p=0.052) Rate of moderate/severe exacerbation (HR=0.75 95%

CI=0.69 to 0.81 p<0.001) ▪ NNT=4

Rate of severe exacerbation requiring hospital (HR=0.83 95% CI=0.71 to 0.98 p<0.03)

Requirement systemic steroid (HR=0.57 95% CI=0.51 to 0.64 p<0.001)

FEV1 difference 0.092 (p<0.001) SGRQ change in score -3.1 (-4.1 to -2.1 p<0.001)

Results (FP/SALM vs SALM) Risk of death (HR=0.932, 95% CI=0.765 to 1.134; p=0.48) Rate of moderate/severe exacerbation (HR=0.88 95%

CI=0.81 to 0.95 p<0.002) Rate of severe exacerbation requiring hospital (HR=1.02

95% CI=0.87 to 1.20 p=0.79) Requirement systemic steroid (HR=0.71 95% CI=0.63 to

0.79 p<0.001) FEV1 difference 0.050 (p<0.001) SGRQ change in score -2.2 (-3.1 to -1.2 p<0.001)

FEV1 Dyspnea QOL Exacerbation Rate

Calverley 2007 FP/SALM vs SALM

n/a Improved

Calverley 2003 FP/SALM vs SALM

Improved Improved

Mahler 2002 FP/SALM vs SALM

~ Improved ~ n/a

Hanania 2003 FP/SALM vs SALM

~ ~ n/a

Szafranski 2003 BUD/FORM vs FORM

~ ~ ~

Fluticasone furoate/vilanterol 100/25mcg once daily

Adverse effects Nasopharyngitis, URTI, Headache, Oral

candidiasis Drug interactions CYP 3A4 inhibitors (ketoconazole) increase

fluticason effects Hepatic impairment (moderate-severe ) No dose adjustment but 3X exposure to FF

SABA + SAMA

LABA + LAMA

Medication Device Dose Frequency

Combivent Respimat® (albuterol/ipratropium) MDI 100 mcg/20 mcg 1 INH QID

DuoNeb® (albuterol/ipratropium) NEB (2.5 mg/0.5 mg)/ 3 mL 1 NEB QID

Medication Device Dose Frequency

Anoro Ellipta® (umeclidinium/vilanterol) DPI 62.5/25 mcg 1 INH daily

Stiolto Respimat® (tiotropium/olodaterol) MDI 2.5/2.5mcg 2 INH daily

Utibron Neohaler® (Indacaterol/ Glycopyrrolate)

DPI 27.5/15.5mcg 1 INH bid

GOLD 2015; Lexi-Drugs

Umeclidinium/vilanterol 62.5/25mcg once daily

Adverse effects Pharyngitis, sinusitis, LRTI, diarrhea, constipation,

extremity pain, muscle spasm, neck & chest pain Additive AE’s with SAMA or LAMA

Tiotropium/olodaterol 2.5/2.5mcg once daily Adverse effects Pharyngitis, back pain, cough

Additive AE’s with SAMA or LAMA

Indacaterol/Glycopyrrolate 27.5/15.5mcg twice daily

Adverse effects Nasopharyngitis, hypertension

Roflumilast (Daliresp®) GOLD 3 & 4 500mg tab once daily Adverse effects ▪ GI (diarrhea, wt loss, nausea) ▪ Headache, dizziness, insomnia

Drug interactions ▪ CYP 3A4 inhibitors (cimetidine) increase effects ▪ CYP 3A4 inducers (rifampin) decrease effects

GOLD 2015

Inhaled steroids may be useful in GOLD 3 & Stage 4 exacerbations symptoms, lung function, & QOL risk of pneumonia

Combination therapy with LABA is more effective than individual agents

GOLD 2015; Calverley PM, et al. NEJM 2007; Crim C, et al. Eu Respir J 2009

Leuppi JD, et al. JAMA 2013 Treatment ▪ 40mg po daily X 5 days vs 14 days Primary Endpoint ▪ Time to next exacerbation in 6

months Results ▪ HR 0.95 (90% CI, 0.70 to 1.29)

GOLD 2015

Aclindinium/formoterol Mometasone/formoterol Vilanterol Ipratropium/Fenoterol

“There are well designed studies that demonstrate that the medicine has to be in you

to be effective”

Dr. Wayne Samuelson, MD Professor of Medicine

University of Utah University of Utah Adult Asthma Center Director

50% of adults and children do not perform all steps correctly (Crompton GK. Lung 1990;Suppl 168:658-662)

Reasons for noncompliance Not taking off cap Not shaking Failure to coordinate actuation with inspiration Inhale through nose and not mouth Inhale too fast Failure to breath-hold after dose “Cold freon” effect Holding MDI upside down

Plaza et al. Resp 1998;65:195-198 9% of patients, 15% of nurses, and 28% of

physicians showed correct MDI-technique. Interiano et al. Arch Intern Med 1993;153:81-

85 65% of patients, 39% of housestaff, 82% of

nurses were categorized as having “poor” MDI-technique.