Obstructive Lung Disease

Margaret M. Johnson, MD Associate Professor of Medicine

Chair, Division of Pulmonary Medicine Mayo Clinic Florida

Johnson.margaret2@mayo.edu

16 November 2013

Santiago. Chile

Abbreviations

• ICS-Inhaled corticosteroids

• LABA-long acting beta agonists

Overview • Asthma

– Paradigm shift form “severity” to “control”

– Beta agonist safety concerns • Increased steroids v. addition of long acting beta agonist

– Anticholinergic therapy

• COPD

– New GOLD Guidelines

– Update in exacerbation prevention and management

• Bronchiectasis

– The role of macrolides

– Cautions with use

Assessment of Asthma Severity to Guide Therapy

• Paradigm switch from severity to “control” to guides changes in therapy

– Needs frequent re-assessment

• Components of control

– Daytime symptoms

– Nocturnal symptoms

– Limitation to activity

– Need for rescue use

– Lung function or peak flow variability

Assessment of Control

Characteristic Controlled

(All of following)

Partly controlled

(Any measure present) Uncontrolled

Daytime symptoms

≤2X/week >2x/week >3 features of poorly

controlled

Nocturnal symptoms

None Any

Activity limitation

None Any

Rescue use ≤2X/week >2x/week

Lung function Normal <80% predicted or

personal best

GINA Report March 2013.

Pharmacological Therapy in Asthma

National Asthma Education and Prevention Program 2007.

www.ginasthma.org.

Why the Concerns about Long Acting Beta Agonists?

SMART Trial

• Double-blind, randomized observational trial *28 weeks in 26,000 patients

• Salmeterol or placebo added to “usual care”

• Salmeterol associated with greater asthma related deaths and life threatening exacerbation in African American population

– Difference not seen in second half of recruitment which was from physicians’ practices rather than mass advertising

• No difference in outcomes in Caucasians

Nelson, Chest 2006.

Benefits of Long Acting Beta Agonists

• Improve lung function1

• Improve symptoms

• Improve asthma control2

• Both severe and mild exacerbations deceased when long acting beta agonists areused with ICS3

1. Greening Lancet, 1994;

2. Bateman AM J Resp Crit Care Med, 2004; 3. Pauwels, NEJM, 1997.

Long Acting Beta Agonists in Asthma – Clinical Caveats

• Don’t use without ICS

• Don’t use without ICS

• Use with ICS

• Step down therapy once achieved

• Inform patient of concerns

– Safety concerns have been seen in asthma

• Don’t use without ICS

Is Tiotropium Additive for Uncontrolled Asthma?

• 3-way, double-blind, triple-dummy crossover trial in adults not controlled on ICS

• Addition of tiotropium compared with

– Doubling ICS

• Primary superiority comparison

– Addition of LABA (salmeterol)

• Secondary non inferiority comparison

• Primary outcome: Morning peak expiratory flow

Peters SP. N Eng J Med 2010;363:1715-26.

Peters SP. N Eng J Med 2010;363:1715-26.

Overall, Outcomes Favored Tiotrpopium

12

COPD

New GOLD Guidelines

Exacerbations

Impact

Prevention

Treatment

New Classification of COPD

• Characterization based upon

– Impact on health status

• Symptoms & functional limitations

– Severity of airflow limitation

– Risk of future exacerbations

• Grade of Airflow limitation (FEV1/FVC < .70)

– 1 Mild FEV1 > 80% predicted

– 2 Moderate FEV1 >50% & < 80% predicted

– 3 Severe FEV1 > 30% & < 50% predicted

– 4 Very severe FEV1 < 30% predicted

Combined COPD Assessment

Group C GOLD Grade 3-4 and/or 2 exacerbation/year and/or 1 hospitalization/year ICS + long-acting beta agonist or long-acting anticholinergic

Group D GOLD Grade 3-4 and/or 2 exacerbation/year and/or 1 hospitalization/year ICS + long-acting beta agonist or long-acting anticholinergic

Consider “triple therapy”

SYMPTOMS mMRC > 2 CAT > 10

mMRC < 2 CAT< 10

RIS

K

Group A

GOLD Grade 1-2 0-1 exacerbation/year Short-acting beta agonist or short-acting anticholinergic

Group B

GOLD Grade 1-2 0-1 exacerbation/year Long-acting beta agonist or long-acting anticholinergic

Exacerbation

• Impact

– Associated with more rapid lung function loss

– Failure to regain “pre-attack” functional status

• Definition

– “Significant and persistent worsening of dyspnea in setting of COPD…necessitating a change in therapy”

• May or may not require hospitalization

Exacerbation: Prevention • Inhaled steroid + long acting beta agonist

– 4 arm trial n > 6,000 subjects » TORCH Trial N Engl J Med 2007; 356:775-778

• Tiotropium

– Tiotropium or placebo added to current care

– 60% were on either inhaled steroids or long acting beta agonist

» UPLIFT Trial N Engl J Med 2008; 359:1543-1554

• Inhaled steroid + long acting beta agonist added to tiotropium

• “Triple Therapy” » Aaron SD Ann Int Med 2007;146 (8):545

Exacerbation: Prevention

• Addition of Roflumilast

– Oral phosphodiesterase inhibitor

– Reduced frequency of exacerbations needing steroids

– More side effects

» Mostly gastrointestinal » Calverley PM. Lancet 2010;376:1146

• Daily Azithromycin (n= 1142)

– Longer time to first exacerbation compared with placebo

– Greater percentage of people with clinically meaningful • ? Maybe only three times/week

» Albert RK. NEJM 2011;365:689

Caution: Azithromycin and Cardiac Death

• Review of 350,000 prescriptions for azithromycin in Tennessee database

– Patients without severe cardiac disease

• Comparison with cohort of no antibiotic use and other antibiotics

• Absolute increase in cardiac death of 29 in those who received azithromycin

– Absolute excess risk of 1 in 20,000

• Check baseline Qtc (?)

Ray, WA New Eng J Med 2012:366:1881-1890

Exacerbation: Treatment

• Systemic steroids

– REDUCE Trial

• Randomized trial (n=314)

• 5 days v. 14 days of prednisone 40 mg

• Shorter course NONINFERIOR in time to next exacerbation

– Shorter hospital course (1 day)

» Jorg D. JAMA 2013; 309(21):2223

Bronchiectasis

Treatment

• Infection

– Avoidance-appropriate vaccinations

– Treat acute flares

• Common pathogens – Pseudomonas

– H. influenza

– S. aureus

– Maintenance therapy

• Scheduled use of oral or inhaled antibiotics – Example-antibiotic therapy first 7-10 days of month

– 2 or 3 agents used in rotating fashion

– No prospective data to support

Surgical Treatment

• Surgery

– Resection for localized disease

– Resection of foreign body with subsequent bronchiectasis

– Transplant

Macrolide therapy in Non-CF Bronchiectasis

• EMBRACE-Lancet 2012

– Radiographic bronchiectasis & > 1 exacerbation

– Azithromycin 500 mg 3/week v. placebo ( n= 141) for 6 months

– Fewer exacerbations with azithromycin

• Rate ratio 0.38, CI 0.26-0.54, p <0.001

– No difference in lung function or quality of life

Wong C. Lancet 2012;380:660-667

Macrolide therapy in Non-CF Bronchiectasis

• BAT-JAMA 2013

– Non-cystic fibrosis bronchiectasis & >3 lower respiratory tract infections in prior year

– Azithromycin 250 mg daily v. placebo (n=83) * 1 year

– Fewer exacerbations but more azithromycin resistance

– Gastrointestinal side effects were common but rarely required discontinuation

Altenburg J. JAMA 2013;309:1251

Macrolide therapy in Non-CF Bronchiectasis

• BLESS-JAMA 2103

– Bronchiectasis and > 2 infectious exacerbations in prior year

– Erythromycin 400 mg PO twice daily or placebo * 1 yr (n= 117)

– Reduced exacerbation rate overall and in subgroup with pseudomonas colonization

– Reduced rate of lung function decline

Serisier DJ. JAMA 2013;309:1260

Macrolide therapy in Non-CF Bronchiectasis: Cautions

• Cardiac rhythm abnormalities

– Prolonged Qtc

– Association with sudden death

• Risk of inducing macrolide resistant non tuberculous mycobacterial disease

Take Home Points: Asthma • Step-up and step-down therapy based on

frequent re-assessment of control

– Day and night symptoms, activity level rescue inhaler use, lung function

• Safety concerns with long acting beta agonists

– Don’t use without other controller therapy like inhaled corticosteroids

• Tiotropium has been shown to have beneficial effects in those not controlled on inhaled steroids

Take Home Points: COPD

• New GOLD classification focused on severity of disease, symptoms, and risk or exacerbations

• Prevention of exacerbations • “Triple Therapy”

• Roflumilast

• Daily azithromycin

• Shorter course of steroids (5 days) appears NONINFERIOR to 14 day course

Take Home Points: Bronchiectasis

• Prevention and treatment of infections if central to successful management

• Surgery is useful for localized disease

• Macrolide therapy demonstrated to have beneficial effect

• Cautions:

»Cardiac rhythm abnormalities

»Development of resistant Nontuberculous mycobacterial infections