Download - 0900- Johnson Obstructive Lung Dz
Obstructive Lung Disease
Margaret M. Johnson, MD Associate Professor of Medicine
Chair, Division of Pulmonary Medicine Mayo Clinic Florida
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