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, 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 FE V Oxygen therapy
1 Supplemental Therapy Pulmonary rehab Short-acting inhaled bronchodilator for acute relief of symptoms Combination of inhaled corticosteroid, long-acting -agonist, and long-acting anticholinergic Combination of anticholinergic
and -agonist bronchodilator Stepwise Drug Therapy Pneumococcal and annual influenza vaccination, smoking cessation and regular assessment of lung function o Sympt ms 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 2-adrenergic receptors, increasing cyclic AMP and relaxing airway smooth muscle Short-acting agent
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 2-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 2 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 patients 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
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 Veterans 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 corticosteroids C. Oxygen D. 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 corticosteroids C. Long-acting inhaled anticholinergics D. 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.
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