COPD: Patient Intervention
Peter J. Carek, MD, MS
Program Director, Trident/MUSC Family Medicine Residency,
Charleston, SC
Lori M. Dickerson, PharmD
Associate Program Director, Trident/MUSC Family Medicine Residency,
Charleston, SC
Educational Objectives
At the end of this presentation, the learner should
be able to …
• Discuss the pharmacologic treatment of chronic
obstructive pulmonary disease (COPD)
• Manage acute exacerbations
• Evaluate components and effectiveness of
COPD disease management programs and
group visits
• Provide instruction in use of patient diaries
Pharmacologic Therapy
Goals
•
•
•
•
Prevent and control symptoms
Reduce frequency and severity of exacerbations
Improve health status
Improve exercise tolerance
Oxygen therapy
Supplemental
Therapy
Pulmonary rehab
Short-acting
inhaled
bronchodilator
for acute relief
of symptoms
Combination of inhaled corticosteroid, long-acting
β-agonist, and long-acting anticholinergic
Combination of anticholinergic
and β-agonist bronchodilator
Stepwise
Drug Therapy
Pneumococcal and annual influenza vaccination, smoking cessation
and regular assessment of lung function
Health Care Maintenance
Adapted from Sutherland, 2004
Pharmacologic Therapy
Oxygen therapy
• Used as long-term continuous therapy, during exercise,
or to relieve acute dyspnea
• Improves survival in COPD patients with severe
hypoxemia (partial pressure of oxygen [pO2] < 55 mm Hg
or oxygen saturation [sO2] <88%) (Strength of
Recommendation [SOR]: A)
– When used for >15 hours daily
• Does not improve survival in patients with moderate
hypoxemia or desaturation at night
Cranston, 2008
GOLD, 2009
Pharmacologic Therapy
Oxygen therapy
• Candidates include patients with very severe COPD who
have walking pO2 …
– ≤ 55 mm Hg or oxygen saturation less than 88%, with or without
hypercapnia (SOR: B)
– between 55 and 60 mm Hg with pulmonary hypertension,
peripheral edema suggesting heart failure, or polycythemia
(hematocrit > 55%) (SOR: C)
Cranston, 2008
GOLD, 2009
Pharmacologic Therapy
Oxygen therapy
• Titrate to pO2 of at least 60 mm Hg or oxygen saturation
of at least 90%.
• Beware of pushing O2 saturation too high - can turn off
the respiratory drive in CO2 retainers
Cranston, 2008
GOLD, 2009
Pharmacologic Therapy
Bronchodilators
• Foundation of symptomatic treatment
– Improve airflow and hyperinflation, decrease work of breathing
and improve exercise tolerance
– Do not slow the progression of COPD (SOR: B)
• Types
– Beta2-agonists (long-acting, short-acting)
– Anticholinergics (long-acting, short-acting)
– Combinations
GOLD, 2009
Pharmacologic Therapy
Beta agonists - Mechanism of action
 Stimulate ß2-adrenergic receptors, increasing cyclic AMP and
relaxing airway smooth muscle
Short-acting
agent
Inhaler (mcg/puff)
Cost
Solution
Cost
Albuterol
MDI (90)
$
0.63, 1.25 mg/3 mL; 2.5
mg/0.5 mL; 2.5 mg/3 mL
$$
Levalbuterol
MDI (45)
$
0.31, 0.63, 1.25 mg/3 mL
$$$$$
Salmeterol
DPI (50)
$$$
NA
—
Formoterol
DPI (12)
$$$
20 mcg/2 mL
$$$$$
Aformoterol
NA
—
15 mcg/2 mL
$$$$$
MDI = metered dose inhaler; DPI = dry powder inhaler; NA = not available.
Rabe, 2007; GOLD, 2009
Pharmacologic Therapy
Anticholinergics - Mechanism of action
 Block effect of acetylcholine on muscarinic-type 3 receptors,
resulting in bronchodilation.
Agent
Inhaler (mcg/puff)
Cost
Solution
Cost
MDI (17)
$
0.5 mg/2.5 mL
$$
DPI (18)
$$$
NA
—
MDI (90 + 18)
$$$
2.5 + 0.5 mg/3 mL
$$$$
Short-acting
Ipratropium
Long-acting
Tiotropium
Combinations
Albuterol +
Ipratropium
MDI = metered dose inhaler; DPI = dry powder inhaler; NA = not available.
Rabe, 2007; GOLD, 2009
Pharmacologic Therapy
Short-acting bronchodilators
• Used “as needed” for all stages of COPD (SOR: A)
• Albuterol or Ipratropium
– Longer duration of action with ipratropium (6-8 hours) than
albuterol (4-6 hours) (SOR: A)
– Ipratropium not used alone for rescue, but is used for
maintenance.
• Combination slightly better bronchodilation than
either agent alone (SOR: A)
Rabe, 2007
GOLD, 2009
Pharmacologic Therapy
Long-acting bronchodilators
• For moderate airflow limitation, use scheduled
long-acting bronchodilator
– Relieve symptoms, increase exercise tolerance,
reduce exacerbations, improve quality of life (SOR: A)
– Once- or twice-daily dosing
• Must be given with short-acting bronchodilator
for acute relief of symptoms
Rabe, 2007
GOLD, 2009
Pharmacologic Therapy
Bronchodilator - Adverse effects
• ß2-agonists
– Tachycardia, palpitations, muscle tremors/cramping,
insomnia
– Hypokalemia, prolonged QT interval, hyperglycemia
– Levalbuterol offers no advantage to albuterol (SOR: A)
• Anticholinergics
– Dry mouth, constipation
• Similar adverse effects with short- and longacting agents
Rabe, 2007
GOLD, 2009
Pharmacologic Therapy
Long-Acting β2 Agonists (LABAs)
• No evidence of tolerance with regular use (SOR: A)
• No known difference among agents (salmeterol,
formoterol, aformoterol)
• Can use short-acting anticholinergic or beta2-agonist
for relief of symptoms
Rabe, 2007
GOLD, 2009
Pharmacologic Therapy
Long-acting anticholinergics
• Tiotropium has once daily dosing, duration of action > 24
hours (SOR: A)
• In patients with moderate to severe COPD
– Delayed time to first exacerbation (16.7 vs. 12.5 months)
– Reduced exacerbation days per patient-year (12.11 vs. 13.64)
– Did not affect mortality
• Insufficient evidence to recommend one long-acting
bronchodilator over another
– Tiotropium vs. salmeterol
Tashkin, 2008
GOLD, 2009
Pharmacologic Therapy
Long-acting anticholinergics
• Short-acting beta2-agonists (ie, albuterol) are
recommended for relief of symptoms (SOR: A)
• Should not use short-acting anticholinergics (ie,
ipratropium) for relief of symptoms if also using
long-acting anticholinergic
Kerstjens, 2007
GOLD, 2009
Pharmacologic Therapy
Anticholinergics and cardiovascular events
• In meta-analyses, anticholinergic agents have
been associated with cardiovascular events
– Ipratropium > tiotropium (SOR: B)
– Significant limitations to study
• Large, prospective randomized controlled trial of
tiotropium found no association with
cardiovascular events
Singh, 2008
Celli, 2010
Ogale, 2010
Pharmacologic Therapy
Inhaled bronchodilators - Summary
• Stick with the GOLD guidelines
– Use short-acting bronchodilators as needed for
symptoms (SOR: A)
– When regular use is needed, long-acting
bronchodilators are more effective and convenient
(SOR: A)
• Consider the patient’s baseline cardiovascular
risk before prescribing an anticholinergic
(SOR: C)
• Encourage smoking cessation
Pharmacologic Therapy
Theophylline
• Oral bronchodilator
• May be used if:
– Symptoms continue despite combined inhaled bronchodilators (SOR: B)
– Cost of inhalers prohibits their use
• Rarely done because:
– Toxicity (elderly, liver disease, heart failure)
– Frequent monitoring to maintain levels within narrow therapeutic range
(5-12 mcg/mL)
– Adverse reactions
– Drug interactions (metabolized via CYP 1A2, CYP 3A4)
• Use slow-release products (available in generic)
Rabe, 2007
GOLD, 2009
Pharmacologic Therapy
Corticosteroids
• Effects much less dramatic in patients with COPD vs.
patients with asthma
– Pulmonary inflammation not prominent in COPD
– Unknown if effects vary by patient or stage of disease
• No longer recommend short course (2 weeks) of oral
steroids to identify COPD patients who might benefit
from inhaled steroids (SOR: A)
– Poor predictor of long-term response to inhaled steroids in
COPD
Rabe, 2007
GOLD, 2009
Pharmacologic Therapy
Corticosteroids
• Long-term oral steroids not recommended for patients
with stable COPD (SOR: A)
• Add inhaled steroids to inhaled bronchodilator(s) in
patients with severe COPD and frequent exacerbations
(SOR: A)
– Statistically significant impact on following indicators
• Frequency of exacerbations
• Quality of life
• Hospitalization rates
– Does not slow progression of COPD
Rabe, 2007
GOLD, 2009
Pharmacologic Therapy
Inhaled corticosteroids (ICS)
• ICS must be used in combination with LABA for
patients with COPD
• ICS monotherapy only FDA approved for treatment of
asthma, not COPD
Agent
Inhaler (mcg/puff)
Cost
Fluticasone/salmeterol
DPI (100/250/500 + 50)
$$$$
Budesonide/formoterol
MDI (80/160 + 4.5)
$$$$
Mometasone/formoterol
MDI (100/200 + 5)
$$$$
DPI = dry powder inhaler; MDI = metered dose inhaler.
Pharmacologic Therapy
ICS - Benefits and harms
• In severe COPD, twice daily combination therapy with ICS
(fluticasone 500 mcg daily) plus LABA (salmeterol 50 mcg daily) vs.
placebo resulted in:
– No effect on quality of life, total mortality or COPD related-deaths
– Reduced frequency of moderate to severe exacerbations, exacerbations
requiring steroids or hospitalization
• Effect size very small (0.03 – 0.34 exacerbations per year difference)
– Increased risk of pneumonia (number needed to harm [NNH] = 14)
• ICS alone increased mortality (NNH = 30) and COPD-related deaths
(NNH = 46) compared with combination therapy
Calverley, 2007
Pharmacologic Therapy
ICS - Benefits
• Meta-analysis confirmed the small impact of ICS on
frequency of exacerbations
– FEV1 < 50% predicted (severe disease)
• Relative risk of exacerbations 0.79 (95% CI, 0.69 – 0.89)
– Over 5-year period, patients with severe disease having 2
exacerbations per year would have 8 instead of 10
exacerbations if they used ICS
– FEV1 > 50% predicted (less severe disease)
• No significant change in exacerbation risk. Relative risk of
exacerbations 1.03 (95% CI, 0.86 – 1.23)
Agarwal, 2010
Pharmacologic Therapy
ICS - Adverse effects
• Local
– Candidiasis and dysphonia
– Rinse after use to reduce risk
• Systemic absorption with high dose
– 1,000 mcg fluticasone per day
– Skin bruising, cataracts, reduced bone mineral
density
Rabe, 2007
GOLD, 2009
Pharmacologic Therapy
ICS - Adverse effects
• Pneumonia
– Increased risk with ICS alone and combination ICS +
LABA (NNH = 14-16)
– Confirmed in large meta-analysis of COPD patients
receiving ICS for at least 24 weeks
• Relative risk of any pneumonia 1.6 (95% CI, 1.33 – 1.92)
• Relative risk of serious pneumonia 1.71 (95% CI, 1.46 –
1.99)
Calverley, 2007
• No increase in pneumonia-related mortality
Singh, 2008
Pharmacologic Therapy
Inhaled Corticosteroids (ICS) - Summary
• Monotherapy should be avoided (SOR: A)
– Monotherapy with LABA appears to be safe
• ICS (alone or in combination) may be harmful (SOR: A)
– Increased risk of pneumonia
• Combination therapy (LABA + ICS) offers little
advantage in terms of exacerbations (SOR: A)
– Reserve for patients with severe COPD (FEV1 < 50% predicted)
(SOR: A)
Pharmacologic Therapy
LABA/ICS vs. Tiotropium
• No difference in frequency of exacerbations or quality of
life when patients with severe COPD given
salmeterol/fluticasone 50/500 mcg twice daily or
tiotropium 18 mcg daily
– Salmeterol/fluticasone associated with exacerbations requiring
antibiotics
– Tiotropium associated with exacerbations requiring oral steroids
Wedzicha, 2008
Pharmacologic Therapy
LABA/ICS plus tiotropium
• Cohort study of Veteran’s Affairs patients with COPD
found:
– LABA/ICS + tiotropium (compared with LABA/ICS alone)
associated with:
• Reduced risk of death (0.60 ; 95% CI, 0.45 - 0.79)
• Reduced risk of rates of COPD exacerbations (0.84; 95% CI, 0.73 0.97)
• Fewer COPD hospitalizations (0.78; 95% CI, 0.62 - 0.98)
– Not a prospective randomized controlled trial
• Limitations, bias
Lee, 2009
Which of the following pharmacologic
treatments has been shown to improve
mortality in patients with COPD?
A.
B.
C.
D.
Short-acting inhaled beta2-agonists
Inhaled corticosteroids
Oxygen
Long-acting inhaled anticholinergics
Which of the following pharmacologic
treatments has been shown to increase
FEV1 long term in patients with COPD?
A.
B.
C.
D.
Short-acting inhaled beta2-agonists
Inhaled corticosteroids
Long-acting inhaled anticholinergics
None of the above
Pharmacologic Therapy
Beta blockers in COPD
• Medical myth – Beta blockers are contraindicated in
COPD
• No significant adverse respiratory effects with cardioselective beta blockers in patients with mild-moderate
reversible airway disease or COPD
– Atenolol, bisoprolol, metoprolol
• Use of beta blockers decreased mortality and
exacerbations in patients with COPD
– Even in absence of overt cardiovascular disease
Salpeter, 2005
Rutten, 2010
Pharmacologic Therapy
Acute exacerbations
• Bronchodilator therapy
– Improve airflow (i.e. FEV1) and symptoms during acute
exacerbations (SOR: A)
– Use short-acting beta2-agonist (albuterol) or combination beta2agonist and anticholinergic
– Metered dose inhaler (MDI) + spacer as effective as nebulized
delivery (SOR: C)
• Training on MDI technique essential
• Coordination in elderly patients may hinder use
• Nebulized delivery provides subjective benefit without difference in
FEV1 in acute exacerbations (SOR: B)
GOLD, 2009
Evensen, 2010
Pharmacologic Therapy
Systemic corticosteroids
• Shorten recovery time, improve FEV1 and
hypoxemia (SOR: A)
• May reduce risk of early relapse, treatment
failure, and length of hospitalization
Rabe, 2007
GOLD, 2009
Pharmacologic Therapy
Systemic corticosteroids
• Oral administration
– In non-critically ill patients, no difference in treatment failure with highdose intravenous steroids (ie, methylprednisolone) vs. low-dose oral
prednisone
– Oral prednisone (30 - 40 mg for 7 to 10 days) (SOR: C)
– Oral corticosteroids highly bioavailable, inexpensive, easy to use
– Preferred for patients with functioning intestinal tract able to take oral
medications
• Intravenous administration
– Reserved for critically ill patients
• No role for inhaled corticosteroids in acute exacerbations
deJong, 2007
Lindenauer, 2010
Pharmacologic Therapy
Corticosteroids - Tapering
• Consider tapering if:
– Treating disease flare in patient taking systemic
steroids prior to flare
– Course lasts more than 2-3 weeks
• Consider not tapering if:
– Course lasts less than 2-3 weeks
– Patient not taking systemic steroids prior to flare
Pharmacologic Therapy
Corticosteroids - Tapering
• Tapering is more an “art” than “science”
• One idea…
– 40 mg daily for 14 days then stop
– If you want to taper (fear of disease rebound, taking
steroids before event), try 60 mg daily for 14 days,
then 40 mg daily for 7 days, then 20 mg daily for 7
days, then 10 mg every other day for 7 days, then
stop.
Pharmacologic Therapy
Antibiotics
• Beneficial for patients presenting with an increase in any
of the following three symptoms (SOR: B)
– Dyspnea
– Sputum volume
– Sputum purulence
• Beneficial for patients with severe exacerbations
requiring mechanical ventilation (SOR: B)
• Treatment should be given for 3-7 days (SOR: C)
Rabe, 2007
GOLD, 2009
Pharmacologic Therapy
Antibiotic Regimens
Definition
Oral Treatment
IV Treatment
Mild exacerbation: no risk
factors for poor outcome
Amoxicillin, doxycycline,
TMP/SMX, azithromycin,
3rd generation
cephalosporin
—
Moderate exacerbation with
risk factor(s)* for poor
outcome
Amoxicillin-clavulanate,
levofloxacin, moxifloxacin
Ampicillin-sulbactam, 3rd
generation cephalosporin,
levofloxacin, moxifloxacin
Severe exacerbation with
risk factors for
Pseudomonas aeruginosa
Ciprofloxacin, levofloxacin
(high dose)
Ciprofloxacin, levofloxacin
(high dose), beta lactam
with P. aeruginosa activity
*—comorbid diseases, severe COPD, frequent exacerbations (> 3/year), antimicrobial use within
past 3 months.
GOLD, 2009
Pharmacologic Therapy
Preventive therapy opportunities
• Vaccination
– Influenza
• Annually for all patients with COPD (SOR: A)
– Pneumococcal
• All patients < 65 years with COPD
• Anyone >65 years old
• All smokers
• Counseling for smoking cessation
Rabe, 2007
GOLD, 2009
Nonpharmacologic Therapy
Disease management
• Effectiveness of COPD management programs
– Trials
• 9 randomized, 1 controlled, 3 uncontrolled before-after
– Results
•
•
•
•
Improve exercise capacity (32.2 min; 95% CI, 4.1 - 60.3)
Reduce risk of hospitalization
Moderately improve health-related quality of life
All-cause mortality did not differ between groups (pooled
odds ratio 0.84; 95% CI, 0.54 - 1.40)
Peytremann-Bridevaux, 2008
Nonpharmacologic Therapy
Disease management
• Improve use of spirometry
• Ensure patients receive adequate vaccines
• Educate patients and provide tools to manage their
COPD
• Refer patients to pulmonary rehabilitation
• Initiate group visits
• Use disease registry of patients with COPD
Nonpharmacologic Therapy
Group visits
• Elements
– Group discussion
– Clinical component
– Develop action plan
Nonpharmacologic Therapy
Group Visits
• Preparation
–
–
–
–
–
–
Secure support of organization's administration
Address billing and any other system issues
Establish health care team
Establish threshold for minimum census for meeting
Recognize not ideal for all patients
Customize sessions to each physician and patient
panel
– Establish procedures for meeting
– Identify comfortable place that has exam room nearby
Nonpharmacologic Therapy
Group visits
• Implementation
–
–
–
–
–
Address billing and any other system issues
Recruit patients
Begin the shared medical appointment
Allow time for private consultation
Document the visit
– Evaluate overall program
– Realize focus on mind and body
Nonpharmacologic Therapy
Group visits
• Common Features
–
–
–
–
Voluntary
Interactive
Care delivery systems - NOT classes
Intended to enlist and validate patients as their own
caregivers
– Efficient and effective
Nonpharmacologic Therapy
Patient diaries
• Should include:
–
–
–
–
Doctor visits, lab test results, and therapy milestones
Symptoms, including mucus production
Use of medication
Any over-the-counter medications taken that week, including
vitamins, herbals, and supplements
– Notes to patient or doctor
• Provide more objective tool for use in treatment
decisions (SOR: B)
Vijayasaratha, 2008
Nonpharmacologic Therapy
Patient education
•
•
•
•
•
Quit smoking
Exercise every day
Eat a healthy diet
Take medicines as directed
Get vaccinated
– Flu shot every year
– Pneumonia shot
References
•
•
•
•
Cranston JM, Crockett A, Moss J, Alpers JH, Cranston JM. Domiciliary
oxygen for chronic obstructive pulmonary disease (Cochrane Review). In:
The Cochrane Library 2008 Issue 4. Chichester, UK: John Wiley and Sons,
Ltd.
Evensen AE. Management of COPD exacerbations [published correction
appears in Am Fam Physician. 2010;82(3):230]. Am Fam Physician.
2010;81(5):607-613.
deJong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HAM, van den
Berg JWK. Oral or IV prednisolone in the treatment of COPD
exacerbations. Chest. 2007;132(6):1741-7.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global
strategy for the diagnosis, management, and prevention of chronic
obstructive pulmonary disease. Bethesda, Md.: Global Initiative for Chronic
Obstructive Lung Disease (GOLD), 2009:1-93.
References - Continued
•
•
•
•
Kerstjens HA, Bantje TA, Luursema PB, et al. Effects of short-acting
bronchodilators added to maintenance tiotropium therapy. Chest.
2007;132(5):1493-1499.
Lee TA, Wilke C, Joo M, et al. Outcomes associated with tiotropium use in
patients with chronic obstructive pulmonary disease. Arch Intern Med.
2009;169(15):1403-1410.
Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin DP.
Cardiovascular safety of tiotropium in patients with COPD. 2010;137(1):2030.
Lindenauer PK, Pekow PS, Lahti MC, Lee Y, Benjamin EM, Rothberg MB.
Association of corticosteroid dose and route of administration with risk of
treatment failure in acute exacerbation of chronic obstructive pulmonary
disease. JAMA. 2010;303(23):2359-2367.
References - Continued
•
•
•
•
Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. Cardiovascular events
associated with ipratropium bromide in COPD. Chest. 2010;137(1):13-19.
Peytremann-Bridevaux I, Staeger P, Bridevaux PO, Ghali WA, Burnand B.
Effectiveness of chronic obstructive pulmonary disease-management programs:
systemic review and meta-analysis. Am J Med. 2008;121(5):433-443.e4.
Rabe KF, Hurd S, Anzueto A, et al., for the Global Initiative for Chronic
Obstructive Lung Disease. Global strategy for the diagnosis, management, and
prevention of chronic obstructive pulmonary disease: GOLD executive
summary. Am J Respir Crit Care Med. 2007;176(6):532-555.
Rutten FH, Zuithoff NP, Hak E, Grobbee DE, Hoes AW. Beta-blockers may
reduce mortality and risk of exacerbations in patients with chronic obstructive
pulmonary disease. Arch Intern Med. 2010;170(10):880-887.
References - Continued
•
•
•
•
•
Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective beta-blockers for
chronic obstructive pulmonary disease. Cochrane Database of Systematic
Reviews 2005, Issue 4.
Singh S, Loke YK, Furburg CD. Inhaled anticholinergics and risk of major
adverse cardiovascular events in patients with chronic obstructive pulmonary
disease: a systematic review and meta-analysis [published correction appears in
JAMA. 2009;301(12):1227-1230]. JAMA. 2008;300(12):1439-1450.
Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary
disease. N Engl J Med. 2004;350(26):2689-2697.
Tashkin DP, Celli B, Senn S, et al., for the UPLIFT Study Investigators. A 4-year
trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med.
2008;359(15):1543-1554.
Vijayasaratha K, Stockley RA. Reported and unreported exacerbations of
COPD: analysis by diary cards. Chest. 2008;133(1):34-41.