11/17/2009

COPD and Asthma

Update and Controversies
Beyond the Guidelines

Daryl G Morrical MD, FCCP

Financial Disclosures
 Speaker for GSK
 Multiple lunches from reps for Advair,
Symbicort Spiriva
Symbicort,
 No pens or paper pads from those
companies

1
 11/17/2009

Overview
 Definitions
 Scope of problem
 Long acting beta agonists
 Anticholinergics
 Inhaled steroids

Asthma Definition
Asthma is a chronic inflammatory disorder
of the airways in which many cells and
cellular elements play a role. The chronic
inflammation is associated with airway
hyperresponsiveness that leads to recurrent
episodes of wheezing, breathlessness, chest
tightness, and coughing, particularly at
night or in the early morning. These
episodes are usually associated with
widespread, but variable, airflow obstruction
within the lung that is often reversible either
spontaneously or with treatment.
Global Initiative for Asthma (GINA) Report 2007

Asthma
 Described by Hippocrates in 450 B.C.
 23 million Americans have asthma - 7% of adult
population
– 75% increase in prevalence 1980 to 1994
– 50% or more have poorly controlled asthma
– 6.8 million children
 500,000 hospitalizations per year
 3884 deaths in 2005 (18% decrease since 1999)
 Total health care cost greater than $19 billion

American Lung Association Data 2008

2
 11/17/2009

Etiology
Interaction between host factors and environment
 Balance between Th1 (infection fighting) and Th2
(allergic response) immune response
 Genetics complex and not yet well defined
 Airborne
Ai b allergens
ll (house
(h dust
d mite,
i Alternaria)
Al i ) and
d
viral infection (RSV, rhinovirus) appear most
important environmental factors
– Tobacco smoke, air pollution, diet investigated
 Bacterial infection of airways at young age may
play role

Hygiene Hypothesis
 Exposure to infection early in life influences
development of immune system along
“nonallergic” pathway
 Children with older siblings and daycare
attendance at increased risk infection but
decreased risk allergies and asthma
 Examples of mice in germ free
environments, Australian Aborigines
– Contradictory evidence exists

Hygiene Hypothesis
Factors favoring Th1 Factors favoring Th2
– Older siblings
– Daycare
– TB, measles, hepatitis A
– Rural environment
– Widespread antibiotics
– Western lifestyle
– Urban environment
– Diet
– House dust mite, cockroach
sensitivity

Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NIH, NHLBI. August 2007.
NIH publication no. 08-4051.

3
 11/17/2009

Guidelines for Asthma

Management
 Expert Panel Report 3 (EPR3):
Guidelines for the Diagnosis and
Management
g of Asthma
– Published 2007 by NHLBI/NIH
 Global Initiative for Asthma (GINA)
– Collaborative effort of NHLBI, NIH, WHO
– Updated 2008

Guidelines for Asthma

Management
 New guidelines focus on asthma severity
and control
– Severity - intrinsic severity of disease process
– Control - degree to which manifestations of
asthma are minimized and goals met
 Asthma classified into intermittent and
persistent (mild, moderate, severe)
categories
 Controlled, partly controlled, or uncontrolled

4
 11/17/2009

Goals of Asthma Treatment

 Reduce impairment
– Prevent chronic symptoms, reduce use of
short acting beta agonists, maintain near
normall lung
l function
f ti and d activity
ti it levels
l l
 Reduce risk
– Prevent exacerbations, minimize need for
emergency care or hospitalization,
prevent loss lung function, minimal or no
adverse effects of therapy

Assessment and Monitoring

 Assess asthma severity to initiate therapy
– See asthma severity chart
 Assess control to monitor and adjust
therapy
– Asthma control chart, spirometry every 1 – 2
years
– Sputum eosinophils or exhaled nitric oxide?
 Followup visits
– Asthma control, medication techniques, patient
compliance and concerns, written action plan

Classifying Asthma Severity and Initiating Treatment in

Youths ≥12 Years of Age and Adults
Assessing severity and initiating treatment for patients who are not currently taking long-term control medications
Classification of Asthma Severity ≥12 years of age
Components of
Persistent
Severity
Intermittent Mild Moderate Severe
>2 days/week but Throughout
Symptoms ≤2 days/week
not daily
Daily
the day
Nighttime awakenings ≤2x/month 3-4x/month >1x/week but not nightly Often 7x/week
Short-acting beta2- >2 days/week but
Impairment agonist use for
≤2 days/week
not daily, and not
Daily
Several times
symptom control (not more than 1x on any per day
prevention of EIB) day
Normal FEV1/FVC:
8-19 yr 85% Interference with
None Minor limitation Some limitation Extremely limited
20-39 yr 80% normal activity
40 59 yr 75%
40-59 • Normal FEV1
60-80 yr 70% between
exacerbations
• FEV1 >60% but • FEV1 <60%
Lung function • FEV1 >80% • FEV1 >80% <80% predicted predicted
predicted predicted
• FEV1/FVC reduced • FEV1/FVC
• FEV1/FVC normal • FEV1/FVC normal 5% reduced >5%

0-1 per year ≥2 per year

Exacerbations Consider severity and interval since last exacerbation
Risk requiring oral systemic Frequency and severity may fluctuate over time
corticosteroids for patients in any severity category

Relative annual risk of exacerbations may be related to FEV1

Recommended Step for Step 3 Step 4 or 5

Initiating Therapy Step 1 Step 2 and consider short course of
oral systemic corticosteroids
(See figure 4-5 for treatment steps) In 2-6 weeks, evaluate level of asthma control that is achieved and adjust therapy accordingly.

Asthma EPR 3

5
 11/17/2009

Assessing Asthma Control and Adjusting Therapy in

Youths ≥12 Years of Age and Adults
Classification of Asthma Control (≥12 years of age)
Components of Control
Well Not Well Very Poorly
Controlled Controlled Controlled
Symptoms ≤2 days/week >2 days/week Throughout the day
Nighttime awakenings ≤2x/month 1-3x/week ≥4/week

Interference with normal activity None Some limitation Extremely limited

Short-acting beta2-agonist use for

≤2 days/week >2 days/week Several times per day
symptom control (not prevention of EIB)
Impairment >80% predicted/personal 60-80% predicted/ <60% predicted/
FEV1 or peak flow best personal best personal best

Validated questionnaires

ATAQ 0 1-2 3-4

ACQ ≤0.75 ≥1.5 N/A
ACT ≥20 16-19 ≤15
Exacerbations requiring oral systemic 0-1 per year ≥2 per year
corticosteroids Consider severity and interval since last exacerbation

Risk Progressive loss of lung function Evaluation requires long-term followup care
Medication side effects can vary in intensity from none to very troublesome and
Treatment-related adverse effects worrisome. The level of intensity does not correlate to specific levels of control but
should be considered in the overall assessment of risk.
• Maintain current step. • Step up 1 step and • Consider short course
• Regular followups • Reevaluate in 2-6 of oral systemic
every 1-6 months to weeks. corticosteroids,
Recommended Action for Treatment maintain control. • Step up 1-2 steps, and
• For side effects,
• Consider step down if consider alternative • Reevaluate in 2 weeks.
(see figure 4-5 for treatment steps) well controlled for at treatment options. • For side effects,
least 3 months. consider alternative
treatment options

Asthma EPR 3

Stepwise Approach for Managing Asthma in Youths ≥12

Years of Age and Adults
Persistent Asthma: Daily Medication
Intermittent
Asthma Consult with asthma specialist if step 4 care or higher is required.
Consider consultation at step 3.

Step 6
Step up if
Step 5 needed
Preferred: (first, check
Step 4 Preferred: adherence,
High-dose ICS environmental
Step 3 Preferred:
High-dose control, and
+ LABA + oral
Preferred: Medium-dose ICS + LABA corticosteroid comorbid
Step 2 Low-dose ICS + LABA conditions)

Preferred: ICS + LABA AND

Step 1 OR
Alternative: AND Assess
Medium-dose
L d
Low-dose ICS Medium-dose
control
Preferred: ICS + either Consider Consider
Alternative: ICS LTRA, Omalizumab
SABA PRN Omalizumab for
Cromolyn, Alternative: Theophylline, for patients patients who
who have Step down if
LTRA Low-dose ICS or Zileuton have allergies possible
Nedocromil, or + either LTRA, allergies
Theophylline Theophylline, (and asthma is
well controlled
or Zileuton at least 3
months)
Each step: Patient education, environmental control, and management of comorbidities
Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma
Quick-Relief Medication for All Patients
• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-minute
intervals as needed. Short course of systemic oral corticosteroids may be needed.
• Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control and the
need to step up treatment.
Key: ICS, inhaled corticosteroid; LABA, inhaled long-acting beta2-agonist; LTRA, leukotriene receptor antagonist; SABA,
inhaled short-acting beta2-agonist

Asthma EPR 3

Asthma Control
 No (or < 2x/week) daytime symptoms
 No limitation of activity including
exercise
 No nocturnal symptoms/awakening
 No (or < 2x/week) need for reliever
meds
 Normal or near normal lung function
 No exacerbations
GINA Report 2007

6
 11/17/2009

Classification of Asthma Severity

(When Asthma Well Controlled)

Mild Moderate Severe

Intermittent Persistent Persistent Persistent

Step 1 Step 2 Step 3 or Step 5 or

4 6

Lowest level of treatment required to maintain control

Asthma EPR 3

Asthma Control Test™ (ACT)

1. In the past 4 weeks, how much of the time did your asthma keep you from getting Score
as much done at work, school or at home?

2. During the past 4 weeks, how often have you had shortness of breath?

3. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness
of breath, chest tightness or pain) wake you up at night or earlier than usual in the morning?

4. During the past 4 weeks, how often have you used your rescue inhaler or nebulizer
medication (such as albuterol)?

5. How would you rate your asthma control during the past 4 weeks?

A score of ≤19 means your patient’s asthma may not be under control
ACT is for patients with asthma 12 years and older.
TOTAL
Asthma Control Test is a trademark of QualityMetric Incorporated.
Copyright 2002, by QualityMetric Incorporated.

Lack of Symptom Control in

Asthma
80 75%

60
48%
of Patients

47%

40 32%
%o

20

0
Symptoms in Activity limitation Rescue Missed work
past 4 weeks (sports/recreation) medication use or school
≥ once daily†

Results of a large national telephone survey of 2509 adults with asthma or parents of children
with asthma.
† Patients who used an inhaler for prescription medication (n=1294).

Asthma in AmericaTM, A Landmark Study. Executive Summary. GlaxoSmithKline, December 1998.

7
 11/17/2009

COPD Definition
 Chronic obstructive pulmonary disease
(COPD) is a preventable and treatable
disease with some significant extrapulmonary
effects that may contribute to the severity in
individual patients. Its pulmonary component
is characterized by airflow limitation that is
not fully reversible. The airflow limitation is
usually progressive and associated with an
abnormal inflammatory response of the lungs
to noxious particles or gases.
GOLD Guidelines 2008

COPD Facts
 16 – 24 million in US with COPD

 COPD is the 4th leading cause of death in the United

States (behind heart disease, cancer, and
cerebrovascular disease).
disease)

 In 1990, COPD was the 6th leading cause of death

worldwide; by 2020 it is projected to rank 3rd

 10 year mortality after diagnosis is > 50%

 On average, more die daily from COPD than diabetes or
breast cancer
– 348 per day from COPD, 206 per day from diabetes, 114 per
day from breast cancer

8
 11/17/2009

COPD – Mechanisms of
Injury
 Protease-antiprotease imbalance
 Oxidative stress due to cigarette
smoke or activation of neutrophils and
macrophages
 Apoptosis of endothelial and epithelial
cells from down-regulation of VEGF
 Viral infection

COPD as Systemic Disease

 Smokers with COPD have 2.5X risk for
cardiovascular disease than smokers
without COPD
 Cardiovascular disease was 2nd leading
cause of death in Lung Health Study
 COPD associated with skeletal muscle
dysfunction, cachexia, anemia,
osteoporosis, depression

Guidelines for COPD

Management
 www.goldcopd.org
 First published 2001, last updated
2008
 430 references
 Fewer than 1 in 10 patients with COPD
eligible for studies that form basis for
GOLD guidelines

9
 11/17/2009

COPD Subtypes
Pink Puffer vs Blue Bloater

COPD Subtypes
 Severe and markedly variable airflow
obstruction with features of atopic asthma,
chronic bronchitis, and emphysema
 Features of emphysema alone
 Atopic asthma with eosinophilic airways
inflammation
 Chronic bronchitis in nonsmoker
 Mild airflow obstruction without other
dominant phenotypic features
Lancet August 2009

GOLD Workshop Report

Four Components of COPD
Management
 Assess and monitor
disease
 Reduce risk factors
 Manage stable COPD
– Education
– Pharmacologic
– Non-pharmacologic
 Manage exacerbations

10
 11/17/2009

Classification of COPD Severity

by Spirometry
Stage I: Mild FEV1/FVC < 70%

FEV1 < 80% predicted

Stage II: Moderate FEV1/FVC < 70%
50% < FEV1 < 80% predicted
Stage III: Severe FEV1/FVC < 70%

30% ≤ FEV1 < 50% predicted

Stage IV: Very Severe FEV1/FVC < 70%
FEV1 < 30% (or < 50% with chronic
respiratory failure)

Management Of COPD
Reduce Risk Factors

 Smoking cessation
– Slows rate of pulmonary function decline,
improves cough, improves sense of
t t /
taste/smell,
ll reduces
d risk
i k off lung
l cancer
– Methods -physician instruction and
followup, nicotene replacement,
bupropion (Zyban), varenicline (Chantix),
behavioral modification, accupuncture,
hypnosis
 Most successful quitters go “cold turkey”

Smoking Cessation
 Varenicline (Chantix)
– Partial agonist/competitive blocker of
α4β2 nicotinic receptor
– Nausea in 30-50% of patients – reduced
by taking with food or drink, and gradual
dose increase
– Caution advised in patients with
psychiatric disorders, pilots/air traffic
controllers, heavy equipment operators,
truck drivers

11
 11/17/2009

Smoking Cessation
 Varenicline (Chantix)
– Attempt smoking cessation after one
week of use
– Duration of therapy 12 to 24 weeks
– Reduce dose with renal insufficiency
– 30-55% of users stop smoking
– Cost $3-$4 per day

Strategies to Help with

Smoking Cessation
 ADVISE Strongly urge all tobacco
users to quit
 ASSESS Determine willingness to
make a qquit
it attempt
 ASSIST Aid the patient in quitting
 ASK Systematically identify all
tobacco users at every visit
Phone counseling 1-800-QUIT NOW

 ARRANGE Schedule followup contact

Smoking Facts for U.S.

 Adult smoking rate in US 19.8%
 Economic costs due to smoking
$
$192,775,000,000
, , ,
 392,681 smoking attributable deaths
per year
 Economic cost $10.47 per pack in
direct medical cost and lost
productivity

12
 11/17/2009

Smoking Cessation
 State cigarette excise tax (Jan 2009)
– State average $1.19
– New York $2.75
– South Carolina $0.07
– Indiana $0.995
 Smoking attributable deaths per year
per 100,000 population
– Kentucky 370, Indiana 309, Utah 138

American Lung Association

Indiana Report Card

 Tobacco prevention and control

spending – F
 Smokefree air – F
 Cigarette tax – D
 Cessation coverage – C
 Adult smoking rate 24%
– High School 22.5%, Middle School 7.7%

Effects of Smoking Intervention and the Use of

an Inhaled Anticholinergic Bronchodilator on the
Rate of Decline of FEV1
The Lung Health Study

5887 smokers with airflow limitation randomized to intensive smoking

cessation +/- ipratropium vs. usual care
Bronchodilator had no effect on decline in FEV1

JAMA 1994

13
 11/17/2009

Mortality Rates At 14.5 Years

By Cause

Anthonisen, N. R. et. al. Ann Intern Med 2005;142:233-239

21.7 % in Special Care and 5.4% in Usual Care Group were “Sustained
Quitters”

Mortality Rates At 14.5 Years

By Cause And Smoking Status

Anthonisen, N. R. et. al. Ann Intern Med 2005;142:233-239

Management of COPD
 Attain ideal body weight
 Patient and family education
 Prevent and treat infection
– Pseudomonas more common with severe
COPD
 Bronchodilators
– SABA, anticholinergics

14
 11/17/2009

Management of COPD
Bronchodilators

 Long acting beta agonists (LABA)

– Improve lung function and symptom
control
 Duration 12 hrs with single dose
 Inhalers - salmeterol (Serevent),
formoterol (Foradil)
 Aerosol – aformoterol (Brovana),
formoterol (Perforomist)
 Should not be used alone for asthma

Management of COPD
Bronchodilators

 Anticholinergics
– Ipratropium (Atrovent), tiotropium (Spiriva)
– Ipratropium/albuterol combination
(Combivent, Duoneb)
 Combination of LABA and tiotropium
effective

15
 11/17/2009

Management of COPD
Theophylline
 Bronchodilator – relaxes smooth muscle
 Anti-inflammatory – may affect mucosal
infiltration of eosinophils and T lymphocytes
– May downregulate inflammatory gene expression
 Increases diaphragmatic contractility and
mucociliary clearance
 Toxicities and side effects limit use
– Nausea, diarrhea, arrhythmias, seizures

Corticosteroids and COPD

 Systemic steroids provide modest benefit in
hospitalized pts with exacerbations
– Long term oral steroids should be avoided
 Inhaled steroids have little or no effect on
decline in FEV1 but may improve symptoms
and decrease exacerbations
 ATS recommends inhaled steroids/LABA if 1
or more exacerbations per year and
FEV1<50%
– GOLD has similar recommendation
– NNT to prevent exacerbation 2.1 - 4

16
 11/17/2009

Supplemental Oxygen
 Useful for pO2 < 55 - 60, especially
with end organ dysfunction
 Continuous better than nocturnal
alone
– Prolongs survival
 Compressed gas, concentrator, liquid
all options
 Demand valve system prolongs use
time for portable tanks
 Oxygen cost often $400 - $600 /month

Management of COPD
 Pulmonary rehabilitation
– Exercise, nutritional counseling, education
– Improved exercise duration with no change in
l
lung function
f ti
 Recent studies suggest exercise may slow loss of
function
– Improved quality of life and reduced
hospitalization - psychosocial support
 Treat heart disease – ischemia, arrhythmias,
congestive heart failure

17
 11/17/2009

Management of COPD
 Alpha-1 antitrypsin replacement
– Prolastin, Aralast, Zemaira
– Not all deficient pts develop emphysema
– Cost approx $75,000 per year
 Sleep disordered breathing - may
contribute to cor pulmonale

Surgery for COPD

 Lung volume reduction surgery
– Considered with severe COPD with refractory
symptoms and “target areas” by CXR and CT
– Not considered with hypercarbia, diffuse
emphysema, pulmonary hypertension, and
current or recent smokers
– Generally reported to improve FEV1 by 15 to
35%
– Bronchoscopic techniques being studied (valves)
 Transplantation
– One year survival 75 – 80 %

18
 11/17/2009

Beta Agonist Risk

 Concerns first raised with increased asthma
deaths and high dose isoproterenol aerosols
in 1960’s (UK, Australia, New Zealand)
 Additional concern with fenoterol in 1970’s
(high dose β2 agonist in New Zealand,
Canada)
 Salmeterol and formoterol – selective long
acting β2 agonists – avail since early 1990’s

Beta Agonist Risk

SNS Trial

 Surveillance study of 25,180 asthma

patients in United Kingdom – regular
use of salmeterol vs p
placebo in
addition to other asthma meds
 Improved asthma control but higher
respiratory deaths with salmeterol
(0.07% vs 0.02%, NS)

BMJ 1993

Beta Agonist Risk

Cardiovascular Effects of β-Agonists in Patients with Asthma and
COPD

 Meta-analysis
– 232 pts in single dose trials, and 6,623 pts in
longer duration trial (mean 4.7 months)
 Increase in HR (9 beats/min) and decreased
K (.36 mmol/L) in single dose trials
 Sinus tachy with β-agonist use – also
statistically insignificant increased risk for
VT, syncope, a-fib, CHF, MI, sudden death

Chest June 2004

19
 11/17/2009

Beta Agonist Risk

SMART Trial

 28 week safety trial of salmeterol vs placebo

added to usual asthma care
– 26,335 patients, 6163 sites, 1316 investigators
– Only one initial clinic visit – followup by
telephone
– Recruitment method change during study
– Stopped prematurely due to recruitment and
concern with mortality in African Americans
 No difference in respiratory related deaths
or life threatening experiences overall
Chest 2006

Beta Agonist Risk

SMART Trial

 Increased respiratory related deaths or life

threatening experiences in African
Americans (20 vs 5, RR 4.1)
– Lower peak flows
flows, lower ICS use
use, more ER visits
visits,
more hospitalizations and intubations
 Short acting β agonist use recorded only at
baseline, ICS use not recorded, 60% with
nocturnal symptoms, 20 – 40% with ER visit
within last year, 4 – 8% with prior
intubation
Chest 2006

Beta Agonist Risk

Meta-Analysis: Effects of Adding Salmeterol to Inhaled
Corticosteroids on Serious Asthma-Related Events

 Data from 66 GSK trials, 20,966 subjects

 Salmeterol combined with inhaled steroids
decreases risk severe exacerbations
 No effect on asthma hospitalization or
asthma related deaths or intubations

Ann Int Med July 2008

20
 11/17/2009

Beta Agonist Benefit

Safety of Long-Acting β-Agonists in Stable COPD

 Systematic review with meta-analysis

– 27 studies, 20,527 subjects, LABA vs placebo or
anticholinergic, average FEV1 43% (18 trials with ICS)
 Reduced severe exacerbation (RR .78, NNT 30)
 No difference overall or resp mortality but improved
health related quality of life and airflow
 LABA and inhaled corticosteroids reduced risk resp
death c/w LABA alone (RR .35)
 Tiotropium reduced severe exacerbation compared
to LABA (RR .52)

Chest May 2008

Beta Agonist Risk

 FDA reviewed 110 trials with 60,954
subjects
– 44 deaths/intubations in pts on LABA – 43 of
those in trials that did not mandate use of
inhaled steroids
 Trial to answer question of asthma related
death risk of beta agonist and steroid may
require > 4 million subjects
 May be best to simply avoid long acting β
agonist monotherapy for asthma
Chest August 2009

Beta Agonist Risk

The β Agonist Saga and Its Clinical Relevance: On and
On It Goes

 Why would long acting β agonists

carry risk if short acting are safe?
 β agonists may be propro-inflammatory
inflammatory
 Acute and chronic β agonist effects
may be different
– Other examples of dose effect
 Inotropic treatment of CHF vs beta blocker
 Antiarrhythmic therapy (CAST trial)
Am J Resp Crit Care 2009

21
 11/17/2009

Anticholinergic Risk
Inhaled Anticholinergics and Risk of Major Adverse
Cardiovascular Events in Patients With Chronic Obstructive
Pulmonary Disease

 Meta-analysis - Trials with anticholinergic Rx for

COPD for at least 30 days with report of
cardiovascular outcomes
– 17 trials, 14,783 pts with COPD (6 week to 5 yr followup)
 CV death, MI, or stroke occurred in 1.8% of pts
with anticholinergics and 1.2% of control
 Use of ipratropium or tiotropium associated with
increased MI (1.2% vs .8%, RR 1.53), and
cardiovascular death (.9% vs .5%, RR 1.8)
– Number needed to harm for MI 174
– NNH for CV death 40

JAMA Sept 2008

Anticholinergic Risk
Inhaled Anticholinergics and Risk of Major Adverse
Cardiovascular Events in Patients With Chronic Obstructive
Pulmonary Disease

 No analysis for FEV1, coronary disease,

current smoking status, DM, lipids, statin
use, HBP
 No significant overall mortality risk
 Meta-analysis in Chest 2006 and Thorax
2006 showed no increased mortality risk
with tiotropium

JAMA Sept 2008

Anticholinergic Risk/Benefit
Outcomes Associated With Tiotropium Use in Patients With
Chronic Obstructive Pulmonary Disease

 Cohort Study
– Comparison of historical and contemporary VA
cohorts – total 42,090 pts
 Addition of tiotropium to inhaled steroid and
LABA associated with 40% reduced risk of
death compared to combination of ICS and
LABA with reduced exacerbation rate and
hospitalization
 Other combinations with 2 or meds and
tiotropium assoc with increased mortality
Arch Int Med Aug 2009

22
 11/17/2009

Anticholinergic Benefit
UPLIFT Study

 4 yr double blind trial of tiotropium added to

other meds in 5993 pts, 37 countries
 Mean FEV1 48% pred post bronchodilator
 S ll (47 – 103 ml)
Small l) iimprovementt iin FEV1
but no change in rate of lung function
decline
 Improved quality of life and decreased
exacerbations (RR .86) but 36% of pts
stopped drug or withdrew (rate 44% with placebo)

NEJM Oct 2008

Anticholinergic Benefit
UPLIFT Study

 Mortality for trial period

– 14.4 % in tiotropium group, 16.3% in
p
placebo
 Myocardial infarction
– 67 in tiotropium, 85 in placebo
 Stroke
– 82 in tiotropium, 80 in placebo

NEJM Oct 2008

TORCH Study
 Mortality study with assessment of
exacerbation frequency, health status, and
spirometry
 Comparison
p of combination therapy,
py,
placebo, fluticasone, and salmeterol
– 6112 patients, 444 centers, 42 countries
– FEV1 44% predicted
– Less than 4% mean bronchodilator response
– 43% current smokers
– Nearly 30% had been on steroid/LABA
– 35-45% withdrew from study
 Highest rate in placebo group
NEJM Feb 2007

23
 11/17/2009

TORCH Study
 Mortality rates
– 12.6% in combo, 15.2% in placebo, 13.5% in
salmeterol, and 16% in fluticasone (NS)
– Pulmonary disease accounted for 35% deaths
 27% cardiovascular, 21% cancer
 Slightly improved spirometry (30 ml FEV1)
in combo group, improved health status,
reduced exacerbation rate (NNT 4)
 Increased pneumonia rate in pts on
fluticasone
NEJM Feb 2007

Inhaled Steroid Risk

The Prevention of Chronic Obstructive Pulmonary Disease
Exacerbations by Salmeterol/Fluticasone Propionate or
Tiotropium Bromide

 INSPIRE - COPD exacerbation rate

with salmeterol/fluticasone vs
tiotropium
– 2 year study - 1,323 patients, mean FEV1
39%, 179 centers, 20 countries
– Exacerbation rate 1.28 vs 1.32 per year
– 35% vs 42% withdrew from study
(29% higher on tiotropium)

Am J Respir Crit Care Med 2008

Inhaled Steroid Risk

The Prevention of Chronic Obstructive Pulmonary Disease
Exacerbations by Salmeterol/Fluticasone Propionate or
Tiotropium Bromide

 Mortality 3% in salmet/flutic vs 6% in
tiotrop
 Pneumonia 8% in salmet/flutic vs 4%
in tiotrop
 Improved health status on
salmet/flutic

Am J Respir Crit Care Med 2008

24
 11/17/2009

Inhaled Steroid Risk

Long-term Use of Inhaled Corticosteroids and the Risk of
Pneumonia in Chronic Obstructive Pulmonary Disease

 Meta-analysis of 18 trials
– 16,996 pts, 24 week to 3 yr followup
 Increased risk pneumonia (7.4% vs 4.7%;
RR 1.6)
1 6) and serious pneumonia ( 5.2%
5 2% vs
3.1%; RR 1.71) but no mortality risk (overall or
pneumonia related)
 NNH for serious pneumonia – 47
– Fluticasone at 1000 mcg/day has similar effect on cortisol
as 10mg prednisone/day - doubles risk of pneumonia in
rheumatoid arthritis

Arch Int Med Feb 2009

Inhaled Steroid Benefit

Effect of Fluticasone With and Without Salmeterol on Pulmonary
Outcomes in Chronic Obstructive Pulmonary Disease

 Randomized trial in 114 steroid-naive

pts with stage II or III COPD –
fluticasone vs combination Rx or
placebo – 30 month trial
 Bronchial bx and induced sputums
with analysis of inflammatory cells
– Pulmonary function and methacholine
challenge, dyspnea and health scores
Ann Int Med Oct 2009

Inhaled Steroid Benefit

Effect of Fluticasone With and Without Salmeterol on Pulmonary
Outcomes in Chronic Obstructive Pulmonary Disease

 ICS reduced bronchial T lymphocytes

and mast cells with increased
eosinophils
p and intact epithelium
p
 Reduced fall in FEV1 with improved
hyperresponsiveness, dyspnea, and
health scores
 Addition of LABA improved FEV1

Ann Int Med Oct 2009

25
 11/17/2009

Inhaled Steroid Risk/Benefit

Safety and Efficacy of Combined Long-Acting β-Agonists and
Inhaled Corticosteroids vs Long-Acting β-Agonists Monotherapy
for Stable COPD

 Systematic review – 18 trials, 12,446

subjects
 No changeg in severe exacerbations or
mortality (resp or overall) but small
decrease in moderate exacerbations
(RR .84) and small improvement in
quality of life and FEV1
 Increased pneumonia (RR 1.63)

Chest Oct 2009

Interventions That Work

 Smoking cessation leads to reduced decline
in lung function and reduced mortality
 Oxygen therapy may reduce mortality and
improve quality of life
 Lung volume reduction surgery in patients
with upper lobe emphysema and poor
exercise capacity may improve lung function
and reduce mortality

Conclusions
Medical Therapies
 β agonists have potential for benefit
but also harm
– Should always use ICS with LABA with
asthma and possibly COPD
 Inhaled steroids should be used for all
but intermittent asthma and could be
considered with LABA for severe COPD
patients with frequent exacerbations

26
 11/17/2009

Conclusions
Medical Therapies
 Inhaled anticholinergics are likely safe and
may improve symptoms as well as decrease
exacerbations
 No medications have been shown to prevent
p
the long term loss of lung function with
COPD
 Statin therapy for COPD may improve all
cause mortality and COPD related mortality
 Definition of COPD subtypes will hopefully
better guide therapeutic options

27