Transcript COPD: Risks, Treatment and Mortality Michelle Harkins COPD: Definition “A disease state characterized by airflow limitation that is not fully reversible….usually both progressive and associated with an abnormal inflammatory response of the lungs…..and systemic manifestations.” ATS.

COPD: Risks, Treatment and
Mortality
Michelle Harkins
COPD: Definition
“A disease state
characterized by
airflow limitation that
is not fully
reversible….usually
both progressive
and associated with
an abnormal
inflammatory
response of the
lungs…..and
systemic
manifestations.”
ATS Standards for Diagnosis & management of Patients with COPD (2005)
COPD RISK FACTORS
Genes
Exposure to particles
Tobacco smoke
Occupational dusts
Indoor air pollution
Outdoor air pollution
Lung Growth & Development
Oxidative stress
Gender
Age
Respiratory infections
Previous TB
Low SES
Poor Nutrition
Comorbidities
What percentage of smokers develop
COPD?
A. > 50%
B. 30-40%
C. 15-20%
D. < 10%
E. 95%
Lung Function can be
improved by smoking
cessation.
A. True
B. False
Which of the following has
been shown to improve
mortality in COPD?
A.
B.
C.
D.
E.
Ipratropium
Salmeterol
Oxygen
Lung Volume Reduction Surgery
Inhaled corticosteroids
COPD Pathophysiology
• Airflow obstruction (low FEV1/FVC ratio) is hallmark of
COPD
• Small airway inflammation & alveolar destruction are the
two major pathophysiologic processes
• Hyperinflation a major manifestation
• ↑ FRC or ↓ IC
• Occurs at rest (static) but worsens with exertion
(dynamic)
Overall Mechanisms of
Cigarette Smoke-Induced Lung Damage
Inactivation of
antiproteases
Cigarette
smokederived free
radicals and
oxidants
Lipid
peroxidation
Oxidative
Stress
Antioxidant
genes
Depletion of
antioxidant
defenses
Neutrophil
sequestration
Epithelial
permeability
I
N
J
U
R
Y
Inflammation
‘Susceptibility’
genes
MacNee W. Chest. 2000;117:303S-317S.
Transcription of
proinflammatory
cytokines
COPD in the United States
Age-Adjusted Death Rates* for COPD by State: 1995-1997
Deaths/100,000 Population
Highest 46-61 (11)
High 41-45
(13)
Low 36-40
(13)
Lowest 19-35 (13)
*Morbidity and Mortality: 2000 Chart Book on Cardiovascular, Lung,
and Blood Diseases. May 2000.
Pulmonary Function in COPD
• Spirometry
– Decreased FEV1, FEV1/FVC, FEF25-75%
• Lung volumes
– Increased Total Lung Capacity
– Increased Residual Volume
– Decreased Vital Capacity due to air
trapping
• DLCO—decreased in emphysema due
to lung destruction
14
COPD Classification by
Severity
Severity
FEV1/FVC
Mild
≤ 0.7
FEV1 %
predicted
> 80
Moderate
≤ 0.7
50-79
Severe
≤ 0.7
30-49
Very Severe
≤ 0.7
<30 **
** < 50%predicted plus respiratory failure or clinical signs of right heart failure
Celli BR, et.al. Eur Respir J 23:932, 2004;
Global Initiative for Chronic Obstructive Lung Disease Workshop Report; NHLBI, 2001
Major Developments in the Diagnosis
and Management of COPD
• Fletcher & Peto
• Framingham
•
•
•
•
•
•
•
MRC / NOTT
Lung Reduction Surgery
Anthonosin
Laurell and Erickson
Lung Health I
EROSCOP / LHll
Current Guidelines
Role of progressive airflow obstruction
FEV1 (FVC) is related to all cause
mortality
Oxygen improves survival
Provides minimal improvement
Antibiotics for exacerbations
Protease / anti-protease
Early diagnosis and smoking cessation
Steroid use in COPD
Long-acting beta-agonists &
anticholinergics
Accelerated Lung-Function Decline in COPD
100
Nonsmoker
80
60
Symptoms
40
Disability
20
COPD
Death
0
20
30
40
50
60
70
Age (years)
Adapted from Fletcher CM, Peto R. Brit Med J. 1977;1:1645-1648.
80
90
Average Decrease in FEV1 / year
Males
Females
Former smokers
30 ml/year
22 ml/year
Current smokers
66 ml/year
54 ml/year
Anthonisen NR, et.al. Am J Respir Crit Care Med 166:675-9, 2002.
COPD Disease Progression
Treatment of COPD
• Smoking cessation--most important
• Oxygen therapy--improves mortality
– paO2<55, or 56-59 with pHTN,
polycythemia, cor pulmonale
• Drugs--help improve symptoms
– -agonists, short and long acting
– Anticholinergics, short and long acting
– Theophylline--may stimulate respiratory
center, improve muscle function
– Corticosteroids—inhaled, oral
– Roflumilast—decreases exacerbations
Classes of Drugs in COPD
SABA
Albuterol
Pirbuterol
Levalbuterol
Beta-2
agonists
LABA
SAMA
Salmeterol
Formoterol
Arformoterol
Olodaterol
Ipratropium
Antimuscarinics
LAMA
Tiotropium
Aclidinium
Budesonide
Fluticasone
Mometasone
Roflumilast
Theophylline
ICS
PDEI
GOLD guidelines
Modified Stepwise Approach for COPD
Rx (GOLD)
MILD
MODERATE
SEVERE
VERY SEVERE
FEV1>80%
FEv1 50-79%
FEV1 30-49%
FEV1<30% or failure
Reduce risk factors; Vaccination
Pulmonary Rehab
O2/ Surgery
SABA PRN if respiratory symptoms
LAMA
LABA
ICS, if freq. exac (≥ 2/yr.)
Reduction of Risk Factors:
Reduction of personal exposure to
environmental risk factors, smoking
Fletcher, Peto. Br Med J. 1977, 1:1645
Does Any COPD Drug Improve
Health Status?
• Yes but barely
– Improvement, even when statistically
significant, remains clinically modest
– Commonest measure of health status used
in studies is SGRQ
• Change of -4 units is considered clinically
relevant
The LEGO Approach for Improving
Health Status in COPD
Most efficacious
Least efficacious
ICS
LABA
ICS
LAMA LABA
Does Any COPD Drug Improve
Lung Function?
• Yes but barely
– Improvement, when statistically significant,
is clinically modest
• MCID is 100 mL
– Initial improvement but minimal effect on
rate of decline
The LEGO Approach for Improving
Lung Function in COPD
Most efficacious
Least efficacious
ICS
ICS
ICS
LABA
LAMA
LABA
LABA
LAMA
Does any COPD Drug Confer a
Mortality Advantage?
• Short answer is NO
– But there are nuances
– Nothing consistently does so other than
oxygen
COPD Management
Oxygen Therapy in Stage IV disease
• Improved
survival
• Prevents
progression
of PAH
• Increases
exercise
capacity
Summary
• Inhaled drugs improve exacerbation rates
• Modestly improve health status & lung function
• No clear effect on mortality
• Combo therapy better than mono therapy for
ICS
• Triple inhaler therapy is clinically popular but
understudied.
• Pneumonia risk with ICS
• Unclear significance
• Roflumilast & chronic macrolides ↓ exac. risk
COPD Management
Pulmonary Rehabilitation Programs
• Benefit from exercise training programs
• Improved health status
– ↑ exercise tolerance & QOL
– ↓ dyspnea & fatigue
– ↓ hospitalization & LOS
• ↓ exacerbations
• Improves survival
Acute COPD Exacerbation: Definition
• “Acute increase in dyspnea, cough, and/or sputum
beyond day-to-day variability, sufficient to warrant a
change in Rx”
• Important to control
– health status; disease progression & mortality
ATS Standards for Diagnosis & management of Patients with COPD (2005)
Acute Exacerbations: Classification
• Level 1: Treatment at home (optimal)
• Level 2: Hospitalization
• Sudden increase in symptoms (particularly
dyspnea), physical signs, change in mental
status
• Hypoxemia, hypercapnea
• Significant co-morbidities
• Elderly
• Poor home support
• Inadequate response to outpatient therapy
• ER visit in last 7-14 days
• Level 3: Specialized or ICU care
COPD Management:
Acute Exacerbations
• Relapse Rate 20-40%
• If ER visit : 33% recur within 14 days, 17%
eventually need hospitalization
• Risk of Relapse
•
•
•
•
Low FEV1
Increasing medication use (BDs or steroids)
Prior exacerbations (3 within last 2 years)
Comorbid conditions
Miravitlles M, et.al. Factors associated with increased risk of exacerbation and hospital admission in a
Cohort of ambulatory COPD patients: a multiple logistics regression analysis. Respiration 67:495, 2000.
Acute COPD Exacerbation: Survival
30-d mortality worse than AMI?
Miravitlles M, et.al. Factors associated with increased risk of exacerbation and hospital admission in a
Cohort of ambulatory COPD patients: a multiple logistics regression analysis. Respiration 67:495, 2000
Gunen H, Hacievliyagil SS, Kosar F, Mutlu LC, Gulbas G, Pehlivan E, Sahin I, Kizkin O. Eur Resp J. 2005;
26:234-241.
Acute COPD Exacerbation Treatment
• Oxygen: O2 Sat greater than 87%
• Bronchodilators: Short Acting B2-Agonists vs AntiCholinergics
• Similar increase in FEV1 using either alone; data not
great for both together except more side effects
• Anti-Cholinergics have fewer side effects
• MDI (w/ spacer) probably similar to nebulizer if patient
can do maneuver
• Methylxanthines not very helpful
Suto FJ, Varkey B. Current Opinions Pulm Med 9:117-24, 2002
Acute COPD Exacerbations
• Corticosteroids
• short course improves spirometry, decreases relapse
rate
• Oral and IV probably equivalent if gut working
• 2 week treatment similar to 8 weeks, better than 3
days (IV only) with reduced relapse rate, better gas
exchange, spirometry, and DOE
• Reduced relapse rate, treatment failure maintained
for 6 months (at 6 months no different than
placebo; Niewoehner et.al. NEJM 340:1941, 1999)
• ? inhaled steroids (few studies in exacerbations, use
budesonide)
Low-dose PO Steroids Equally or
More Effective as High-dose IV Rx
• Observational pharmacoepidemiological cohort
– 414 US hospitals of 79,985 pts. with acute COPD exac.
• Propensity matching and adjustment to reduce selection bias
• Low-dose oral steroids: 20-80 mg of oral prednisone daily vs.
high-dose IV steroids 120-800 mg prednisone equivalent daily
Lindenauer et al. JAMA 201 - 303 (23): 2359 Year
Acute COPD Exacerbations
Antibiotics
• Controversial
• Greater “success rate” (lower failure rates) when use
antibiotics
• Anthonisen et.al., Ann Int Med 106:196, 1987
• Adams et.al., Chest 117:1345, 2000
• Daniels et al. AJRCCM 2010 181, 150
• More benefit with worse exacerbation, purulent sputum
• “First line” vs. “newer” antibiotics:
• ? Fewer treatment failures with 3rd line agents, better
cost profile
• More studies now taking into account “ExacerbationFree-Interval” and improved QOL as endpoints (Chodosh
S, CHEST 2005; 2231)
Effect of Abx on Survival
Retrospective
population-based
cohort of 50,000 COPD
pts. in Netherlands
• COPD exac. Rxed
with steroids ± abx
• HR for mortality 0.82
• Median time to next
exacerbation delayed
Roede et al. Thorax 2008: 63:968
COPD Management:
NIPPV in Acute Exacerbations
• Should be offered if patient remains with
respiratory acidosis (pH <7.35) or excessive
breathlessness after optimal treatment
• If eligible and tolerated (80-85%), shown to be
effective and safe for exacerbations with
respiratory acidosis
(Keenan et.al, 2003):
• Decreases symptoms quickly
• Decreases hospital stay
• Decreases intubation and mortality
COPD Management:
NIPPV in Acute Exacerbations
• Need to combine CPAP and PSV/EPAP
• Improves gas exchange by increasing
alveolar ventilation
• Improves work of breathing
• Exclusion criteria
• CV instability
• Uncooperative patient
• Impaired mental status
• Copious secretions / High aspiration risk
• Craniofacial abnormalities
NIPPV
• Successful in reducing ARF and
hospital mortality in DNI patients
• Modified and simplified SAPS II and
albumin can predict success in DNI pts,
above all other variables.
• Not successful in patients with
hypoxemic AFR or in pt with terminal
CA.
Schettino et al. Crit Care Med 2005. 33; 1976-1981.
Prolonged Invasive MV
• Hospital survival rates for IMV in COPD
patients from 31-76% depending on
study
• One year survival rates from 15-57%
• Survival rates 1, 2, 5 yr post IMV at a
specialty center: 68%, 54%,and 25%
– Inversely assoc. with age, LOS in ICU
• NIV may improve survival in selected
patients
Quinnell et al. Chest 2006; 129: 133- 139.
Difficulty weaning
•
•
•
•
Muscle weakness (MIP)
Hypercapnia
Malnutrition
Increasing number of exacerbations
Nava et al. Eur Respir J 1994 1645-1652
From Rabe, KF. NEJM 356:851-854.
Prognosis and Natural History of
COPD
• Factors affecting survival
– Initial functional impairment
– Reversibility of obstruction
– Hypoxemia and hypercapnia
– Cor pulmonale
Average Length of Survival Based
on FEV1
FEV1 (L)
1.4
1.0
0.5
Prognosis (YRS)
10
4
2
Jensen MT, Eur Resp J Nov. 2012
Jensen MT, Eur Resp J Nov. 2012
Predictors of Mortality
• FEV1 -all cause mortality
• BODE index (BMI, obstruction. dyspnea,
exercise capactiy)
• DOSE index (dyspnea, FEV1, smoking status,
exacerbation freq.)
• COTE index (COPD co-morbidity test)
– 1664 pt followed for 51 months and 79 co-morbitidies
identified
– 12 of these negatively affected survival
– Score >4 increased death by 2.2 fold
Divo et al. Am J Respir Crit Care Med 186:155-61
BODE
Score
Variable
0
1
2
3
FEV1, %
predicted
>/= 65
50–65
35–49
</= 35
Dyspnea:
MRC
0–1
2
3
4
>/= 350
250–349
150–249
</=149
> 21
</= 21
6MWD,
meters
BMI
From Celli et al (2004), based on the evaluation of 207 patients with COPD
and the subsequent prospective validation on a similar cohort of 625
patients.
The hazard ratio for all-cause mortality is 1.34 for every one-point increase in
the BODE score. The hazard ratio for respiratory-related mortality is 1.62 for
every one-point increase in the BODE score.
The
REAL
reason
dinosaurs
became
extinct...