treatment of copd does current practice match the evidence

COPD: Patient Intervention

Peter J. Carek, MD, MS Program Director, Trident/MUSC Family Medicine Residency, Charleston, SC

Lori M. Dickerson, PharmDAssociate 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

Pulmonary rehabSupplemental Therapy

Stepwise Drug Therapy

Health Care MaintenanceSymptoms

Combination of inhaled corticosteroid, long-acting β-agonist, and long-acting anticholinergic

Combination of anticholinergic and β-agonist bronchodilator

Short-acting inhaled bronchodilator for acute relief of symptoms

Pneumococcal and annual influenza vaccination, smoking cessation and regular assessment of lung function

FEV1

Adapted from Sutherland, 2004


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


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, 2008GOLD, 2009


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, 2008GOLD, 2009


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 TherapyBeta agonists - Mechanism of action

Stimulate ß2-adrenergic receptors, increasing cyclic AMP and relaxing airway smooth muscle

Short-acting agent Inhaler (mcg/puff) Cost Solution CostAlbuterol 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 TherapyAnticholinergics - Mechanism of action

Block effect of acetylcholine on muscarinic-type 3 receptors, resulting in bronchodilation.

Agent Inhaler (mcg/puff) Cost Solution Cost

Short-acting

Ipratropium MDI (17) $ 0.5 mg/2.5 mL $$

Long-acting

Tiotropium DPI (18) $$$ NA —Combinations

Albuterol + Ipratropium

MDI (90 + 18) $$$ 2.5 + 0.5 mg/3 mL $$$$

MDI = metered dose inhaler; DPI = dry powder inhaler; NA = not available.

Rabe, 2007; GOLD, 2009


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, 2007GOLD, 2009


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



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 long-acting agents



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



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, 2008GOLD, 2009


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, 2007GOLD, 2009


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, 2010Ogale, 2010


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


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


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

COPDRabe, 2007

GOLD, 2009


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 COPDRabe, 2007

GOLD, 2009

Pharmacologic TherapyInhaled 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) CostFluticasone/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.


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


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


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

densityRabe, 2007

GOLD, 2009


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)• No increase in pneumonia-related mortality Calverley, 2007

Singh, 2008


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)


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


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. Short-acting inhaled beta2-agonists

B. Inhaled corticosteroidsC. OxygenD. Long-acting inhaled anticholinergics

Which of the following pharmacologic treatments has been shown to increase FEV1 long term in patients with COPD?

A. Short-acting inhaled beta2-agonists

B. Inhaled corticosteroidsC. Long-acting inhaled anticholinergicsD. None of the above


Beta blockers in COPD• Medical myth – Beta blockers are contraindicated in

COPD• No significant adverse respiratory effects with cardio-

selective 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


Acute exacerbations• Bronchodilator therapy

– Improve airflow (i.e. FEV1) and symptoms during acute exacerbations (SOR: A)

– Use short-acting beta2-agonist (albuterol) or combination beta2-agonist 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


Systemic corticosteroids• Shorten recovery time, improve FEV1 and

hypoxemia (SOR: A)• May reduce risk of early relapse, treatment

failure, and length of hospitalization



Systemic corticosteroids• Oral administration

– In non-critically ill patients, no difference in treatment failure with high-dose 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


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


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.


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 TherapyAntibiotic RegimensDefinition Oral Treatment IV TreatmentMild 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


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 cessationRabe, 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


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


Group visits• Elements

– Group discussion– Clinical component– Develop action plan


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


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


Group visits• Common Features

– Voluntary– Interactive– Care delivery systems - NOT classes– Intended to enlist and validate patients as their own

caregivers– Efficient and effective


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


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):20-30.

• 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.

treatment of copd does current practice match the evidence

Documents