Module A: ANNOTATIONS

Annotation A:     Patient with Suspected or Confirmed COPD Presents to Primary Care

1. Definition and Case Finding of COPD

BACKGROUND

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing. Smoking is the primary risk factor for COPD. Although COPD affects the lungs, it also produces significant systemic consequences.

DEFINITIONS *

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease state characterized by expiratory airflow limitation that is not fully reversible. The expiratory airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.

Chronic bronchitis is defined clinically as a chronic productive cough for 3 months in each of 2 successive years in a patient in whom other causes of productive chronic cough have been excluded.

Emphysema is defined pathologically as the presence of permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis.

Asthma is characterized by variable airflow obstruction and differs from COPD in its pathogenic and therapeutic response, and should therefore be considered a different clinical entity. (See the VA/DoD Clinical Practice Guideline for the Management of Asthma). The high prevalence of asthma and COPD in the general population results in the coexistence of both disease entities in many individuals.

Other conditions: poorly reversible airflow limitation associated with bronchiectasis, cystic fibrosis, and fibrosis due to tuberculosis are not included in the definition of COPD but should be considered in its differential diagnosis.

* Source: American Thoracic Society (ATS)/European Respiratory Society (ERS) in Standards for the Diagnosis and Management of Patients with COPD (ATS/ERS, 2004). www.thoracic.org/copd
Similar definitions may be found in the British Thoracic Society, 1997 and The Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2005 [ www.goldcopd.org]

ACTION STATEMENT

RECOMMENDATIONS

  1. Persons with a history of smoking and the presence of cough or chronic sputum production or dyspnea should be assessed for COPD with spirometry. [C]

RATIONALE

EVIDENCE STATEMENTS

EVIDENCE TABLE

 

Evidence

Source

 QE 

 OQ

 SR

1

Twenty-seven percent of patients over 35 years old were current or ex-smokers who had a chronic cough and a reduced FEV1.

van Shayck, 2002

II-2

Fair

C

2

Significant proportion of patients with chronic bronchitis will develop airflow limitation.

Jonsonn, 1998

II-2

Fair

C

QE = Quality of Evidence; OQ = Overall Quality; SR = Strength of Recommendation (See Appendix A)

Annotation B:     Clinical Assessment

2. Assessment, Testing, and Diagnosis

2.1 Clinical Assessment: History and Physical Examination

BACKGROUND

While the diagnosis of COPD is predicated upon spirometry, a meticulous history and physical examination is a central component of the initial diagnosis and ongoing management of patients with COPD.

ACTION STATEMENT

All patients with known or suspected COPD should have a focused history and physical examination to assess for the presence of airflow limitation.  [I]

RECOMMENDATIONS

  1. The following core elements of the medical history should be evaluated in patients with suspected or proven COPD [I]:
    1. Shortness of breath - patients should quantify their level of dyspnea (resting vs. exertional).  Early in the disease course, patients often complain of exertional dyspnea.  As the disease progresses, exercise tolerance worsens and patients may develop resting dyspnea.
    2. Cough - duration and character of the cough should be quantified.  The presence of a productive cough is a second clinical hallmark of COPD.  This cough is typically initially worse in the morning, but can be present throughout the day.  An isolated nocturnal cough is typically not characteristic of COPD.  Chronic bronchitis is defined by the presence of a persistent cough for at least 3 months for 2 or more consecutive years.
    3. Sputum production - volume (amount) and character (color, thickness) of sputum production should be qualified.  Sputum production is required for a diagnosis of chronic bronchitis.
    4. Risk factor assessment - tobacco use, particularly cigarette smoking, is the primary risk factor for developing COPD.  Use should be quantified in pack-years (number of packs per day x number of years = pack-years).  A 10-pack year history of smoking is considered to be the threshold for development of COPD.  There is no comparable standard for pipes or cigars that may also produce COPD.  Environmental pollutant exposure and occupational exposure to vapors, fumes, or irritants are important secondary risk factors.
    5. Other important elements in the initial evaluation of COPD:
      • Prior medical history of asthma, allergies, or recurrent respiratory illnesses (particularly in childhood)
      • Family history of COPD
      • Self-reported history of prior COPD exacerbations and/or hospitalizations
      • Presence of comorbid conditions, in particular coronary artery disease, congestive heart failure, depression, and anxiety.
  2. The following core elements of the physical examination should be evaluated in patients with suspected or proven COPD [I]:
    1. Vital signs - for patients with COPD, an assessment of pulse oximetry and body mass index (BMI = kg/m2) should be included with the vital signs.
    2. Inspection - clinical observation should be performed to assess for the following elements:
      • Chest wall morphology (e.g., 'barrel-chest'); use of accessory muscles (e.g., 'suprasternal retractions'); pursed-lip breathing (surrogates that suggest airflow limitation); and tracheal tug (sign of hyperinflation)
      • Forced Expiratory Time - patients should be asked to completely empty their lungs following a maximal inspiratory effort 
      • Central cyanosis (a surrogate for oxygen saturation); oxygen desaturation may be present in the absence of cyanosis; cyanosis is indicative of severe desaturation
      • Miscellaneous signs - jugular venous distension suggests elevated right heart pressures; bilateral peripheral edema may suggest cor pulmonale.
    3. Palpation/Percussion - these elements are often unhelpful in patients with COPD, but may be helpful in diagnosing pulmonary hyperinflation.
    4. Auscultation - the following elements should be noted on the cardiopulmonary examination:
      • Breath sounds are often diminished or distant in patients with COPD
      • A widened split second heart sound is suggestive of cor pulmonale

EVIDENCE STATEMENTS

2.2 Spirometry and Reversibility for Diagnosis

BACKGROUND

Chronic expiratory flow limitation is the hallmark of COPD.  The diagnostic criteria require documentation of airflow limitation by spirometry.  Since the flow limitation is at most partially reversible, the diagnosis is based on post-bronchodilator spirometric FEV1 and forced vital capacity (FVC) or vital capacity (VC).  Spirometry is sufficient for documentation of expiratory flow limitation.  Lung volumes and diffusing capacity are not required or necessary for documentation of expiratory flow limitation in most patients.  Performance of follow-up spirometry is not routinely indicated since many interventions in COPD are based on symptoms.  Conditions under which spirometry may be indicated include an unexplained change in respiratory symptoms or for preoperative evaluation.

ACTION STATEMENT

Spirometry should be obtained in all stable patients suspected of or having a diagnosis of COPD.  [B]

RECOMMENDATIONS

  1. Spirometry should be performed and documented in the medical record. [B]
  2. A diagnosis of expiratory airflow limitation can be made if the post-bronchodilator FEV1/FVC or FEV1/VC ratio is 0.70 or less.  Where possible, value should be compared to age-related normal values to avoid over diagnosis of COPD in the elderly.  [I]
  3. Reversibility should not be used to predict response to treatment or to distinguish between COPD and asthma.  [B]
  4. Spirometry should be repeated if there is a clinically significant unexplained change in respiratory symptoms.  [I]
  5. All patients presenting with airflow limitation at a relative early age (of the fourth to fifth decade) or with a family history of COPD should be tested for alpha-1-antitrypsin deficiency.  [I]
  6. Oximetry should be considered in patients with COPD and should be performed in all patients with severe or very severe COPD (FEV1 < 50 percent predicted) to determine the degree of hypoxemia and the potential need for long-term oxygen therapy at rest and/or during exercise.  [C]

RATIONALE

EVIDENCE STATEMENTS

EVIDENCE TABLE

    

Evidence

Source

  QE  

OQ

  SR  

1

Perform spirometry (pre- and post-bronchodilator) in all stable patients suspected or having a diagnosis of COPD.

ATS/ERS, 2004

GOLD, 2005

NICE, 2004

III

Poor

B

2

Spirometry is most useful for the diagnosis of patients with severe to very severe COPD.

Wilt et al., 2005

I

Good

A

3

A diagnosis of expiratory airflow limitation can be made if the post-bronchodilator FEV1/FVC or FEV1/VC ratio is < 0.70

ATS/ERS, 2004

GOLD, 2005

III

Poor

I

4

Reversibility does not predict response to treatment or distinguish between COPD and asthma.

NICE, 2004

II-3

Fair

B

QE = Quality of Evidence; OQ = Overall Quality; SR = Strength of Recommendation (See Appendix A)


2.3 Assessing Severity of the Disease

BACKGROUND

The main characteristic of COPD is airflow limitation.  Grading or staging, based on severity of airflow obstruction, facilitates the application of clinical recommendations and attempts to offer a composite picture of disease severity.  FEV1 is the most important physiologic tool used in the diagnosis of COPD as well as in the assessment of its severity, progression, and prognosis.  However, airway obstruction incompletely represents severity of disease.  The 1999 VA/DoD Clinical Practice Guideline for the Management of COPD in Primary Care adopted a classification that is based on both FEV1 and evaluation of symptoms.  This classification is also used by ATS/ERS (2004) and GOLD (2005).  In severe COPD, other manifestations of disease may be better indicators for disease severity and prediction for risk of death.

The COPD severity rating based on FEV1 classifies patients as mild if they have an FEV1 of 80 percent predicted or above.  Most studies evaluating treatment included patients with COPD with an FEV1 exclusively below 70 percent predicted.  The classification is linked to treatment recommendations.  While treatment strategies for patients with FEV1 below 70 percent predicted can be supported by evidence, linking treatment strategies to patients with an FEV1 above 70 percent predicted is speculative, at best.  A recent publication has chosen 70 percent predicted as the dividing line between mild and moderate severity of pulmonary function in patients with obstructive pulmonary disease (Pellegrino et al., 2005).

ACTION STATEMENT

COPD severity should be assessed on the basis of percentage of predicted FEV1 or degree of dyspnea related to activities.  [I]

RECOMMENDATIONS

  1. The forced expiratory volume in one second (FEV1) should be used to stratify disease severity by airflow limitation.  [B]
  2. The Modified Medical Research Council (MMRC) Dyspnea Scale should be used to grade severity of breathlessness according to the level of exertion required to elicit it and help determine treatment.  [C]

Spirometric classification of disease stages and severity is described in Table 1.  The severity of COPD that is based on self-reported symptoms is described in Table 2 using the Dyspnea Scale developed by the Medical Research Council.

Table 1. Severity of COPD Based on Spirometry (adopted from ATS/ERS, 2004)

Stage

Severity

Post-bronchodilator FEV1/FVC

FEV1
% predicted

0

At-Risk (1)

> 0.7

> 80

1

Mild

< 0.7

> 80

2

Moderate

< 0.7

50 – 79.9

3

Severe

< 0.7

30 – 49.9

4

Very Severe

< 0.7

< 30

(1) Patients who smoke or are exposed to pollutants; and have cough, sputum or dyspnea;
    or have family history of respiratory disease.  (There is insufficient evidence to support this category.)

FEV1: forced expiratory volume in one second; FVC: forced vital capacity



Table 2. Severity of COPD Based on Dyspnea (1)

Severity

Score

Degree of Breathlessness Related to Activities

None

0

Not troubled with breathlessness except with strenuous exercise

Mild

1

Troubled by shortness of breath when hurrying or walking up a slight hill

Moderate

2

Walks slower than people of the same age due to breathlessness or has to stop for breath when walking at own pace on the level

Severe

3

Stops for breath after walking approximately 100 meters or after a few minutes on the level

Very Severe

4

Too breathless to leave the house or breathless when dressing or undressing

    • Modified Medical Research Council (MMRC) Dyspnea Scale (Bestall et al., 1999)

RATIONALE

EVIDENCE STATEMENTS

EVIDENCE TABLE

     

Evidence

Source

  QE  

  OQ  

Net Effect

  SR  

1

FEV1 indicates severity of the disease.

Anthonisen et al., 1986

Burge et al., 2003

Celli et al., 2003

Dewan et al., 2000

Ferrer et al., 1997

Friedman et al., 1999

II-2

Fair

Substantial

B

2

Dyspnea is a better predictor of mortality than FEV1.

Nishimura et al., 2002

II-2

Fair

Substantial

C

3

The BMI, Airflow Obstruction, Dyspnea, Exercise Performance (BODE) Index is a better predictor for the risk of death from COPD.

Celli et al., 2004

II-2

Fair

Moderate

B

QE = Quality of Evidence; OQ = Overall Quality;   Net Effect = Size of Intervention Effect; R = Strength of Recommendation (See Appendix A)

Annotation C:     Further Investigation to Exclude Other Diagnoses

2.4 Diagnostic Workup

BACKGROUND

The medical history, physical examination, and spirometry (with reversibility testing) may be sufficient to make a diagnosis of COPD.  However, at the initial visit or as the disease progresses, additional tests may be necessary or helpful to confirm the diagnosis; determine if there are any co-diagnoses such as asthma; define the type of COPD; or assess the severity, physical, and psychological impact of the disease.

ACTION STATEMENT

Other investigations, in addition to spirometry, may be necessary as clinically indicated.  [I]

RECOMMENDATIONS

  1. A diagnosis of COPD requires objective evidence of airflow obstruction via pre- and post-bronchodilator spirometry.  [B]
  2. A chest X-ray should be considered to rule out other diagnoses and for later use as a baseline.  A chest X-ray is not sensitive for the diagnosis of COPD.  [C]
  3. Other investigations may be necessary as clinically indicated [I]:
    1. CT - can exclude other diseases and define bullae and is essential to identify patients eligible for lung volume reduction surgery
    2. Oximetry - should be considered in patients with COPD and should be performed in all patients with severe or very severe COPD (FEV1 < 50 percent predicted) to determine the degree of hypoxemia and the potential need for long-term oxygen therapy at rest and/or during exercise.  Nocturnal pulse oximetry should be performed in patients considered solely for nocturnal oxygen supplementation.
    3. Alpha1-antitrypsin (AAT) - AAT deficiency accounts for less than one percent of COPD.  It should be suspected if there is early onset of COPD, little or no history of smoking, a family history of COPD, or a predominance of basilar emphysema.  If AAT deficiency is suspected, obtain a serum AAT level.
    4. Arterial blood gases - arterial blood gases should be done in patients with very severe COPD (FEV1 < 30 percent predicted); signs of right heart failure (cor pulmonale); polycythemia (hematocrit > 55 percent); or respiratory failure.  Blood gases are an alternative to pulse oximetry in patients being considered for O2 supplementation.  Pulse oximetry can determine arterial oxygen saturation, but pulse oximetry does not yield PCO2.
    5. Full pulmonary function tests - lung volumes, carbon monoxide diffusing capacity and flow-volume loops are not required for routine assessment but can provide additional information useful for resolving diagnostic uncertainty and/or assessing surgical risk.  A reduced carbon monoxide diffusion capacity may suggest the presence of emphysema.
    6. Exercise testing - exercise testing may be of value in patients with a disproportionate degree of dyspnea for their FEV1.  Exercise testing can quantify impairment and/or disability and help to select patients able to safely undergo lung resection.
    7. ECG - to assess cardiac status if pulmonary or nonpulmonary heart disease is suspected or present.
    8. Echocardiogram - to assess right and left cardiac status if cardiac dysfunction or disease is suspected or present.
    9. Sputum cultures - consider in patients with persistently purulent sputum or during recurrent infectious exacerbations.
    10. Complete blood count - should be done if anemia or polycythemia is suspected.

DISCUSSION

COPD and asthma are frequently distinguishable on the basis of history (and examination) in untreated patients presenting for the first time.  Features from the history and examination (such as those listed in Box 1) should be used to differentiate COPD from asthma whenever possible.

Box 1. Clinical Features Differentiating COPD & Asthma
Clinical Features COPD Asthma

Smoker or ex-smoker

Nearly all

Possibly

Symptoms under age 35

Rare

Often

Chronic productive cough

Common

Uncommon

Breathlessness

Persistent and progressive

Variable

Night time waking with breathlessness and or wheeze

Uncommon

Common

Commonly associated with atopic symptoms and seasonal allergies

Uncommon

Common

Significant diurnal or day-to-day variability of symptoms

Uncommon

Common

Favorable response to inhaled glucocorticoids

Inconsistent

Consistent

 

2.5 Referral to Pulmonary Consultant

ACTION STATEMENT

Patients with severe COPD or comorbidity that requires complicated management should be referred to a pulmonary subspecialist.  [I]

RECOMMENDATIONS

  1. Patients with COPD should be referred for consultative opinion if they request it, if there is diagnostic uncertainty, if the disease is very severe or complicated, or if the primary care provider chooses so.  [I]

RATIONALE

Patients with COPD should be referred to a pulmonary subspecialist for any of the following reasons:

3 Prevention - Risk Reduction

Annotation D     Prevention and Risk Reduction

3.1 Patient Education

BACKGROUND

Specific educational packages should be developed for patients with COPD.  Educated patients may be better equipped to cope with the disease and adhere to therapy.  Patients with moderate and severe COPD should be made aware of the benefits and limitations of pulmonary rehabilitation programs. These programs include a component of patient education and self-management training.

Patients at risk of having an exacerbation of COPD should be given self-management advice that encourages them to respond promptly to the symptoms of an exacerbation. The main aim of self-management is to prevent exacerbations by life style adaptations and to allow patients to acquire the skills to treat their exacerbation at an early stage.  Self-management plans need to be structured in a way that takes into account the age and mental status of patients with COPD. There are significant differences in the response of patients with COPD and asthma to education programs.  Programs designed for asthma should not be used in COPD.

RECOMMENDATIONS

  1. Patient should be educated about the disease, cause, therapy, and complications of COPD.  [I]

3.2 Smoking Cessation

BACKGROUND

Tobacco smoking has been shown to cause 80 to 90 percent of COPD cases.  Smoking cessation is the single most effective way to reduce the risk of developing COPD and slow the rate of decline in lung function compared to that of non-smokers.

ACTION STATEMENT

All patients must be screened for tobacco use and encouraged to stop smoking at every visit, as smoking cessation is the only known intervention to reduce the decline in FEV1.  [A]

RECOMMENDATIONS

  1. All patients should be counseled not to smoke and to avoid secondhand smoke.  [A]
  2. All smokers must be told that they need to quit smoking.  [A]
  3. All smokers should be assessed for willingness to quit.  [C]
  4. All smokers should be counseled on smoking cessation and be considered for medications that assist in smoking cessation.  [A]

Table 3. Suggested Strategies to Promote Smoking Cessation: “5 A’s”*
Strategy 1:

Ask: Systematically identify all tobacco users at every visit.  Implement an office wide system that ensures that for every patient at every clinic visit, tobacco use status is queried and documented.
Strategy 2:

Advise: Strongly urge all smokers to quit.  In a clear, strong, and personalized manner, urge every smoker to quit.
Strategy 3:

Assess: Assess smokers willingness to make a quit attempt.  Ask every smoker if he or she is willing to make a quit attempt at this time.
Strategy 4:

Assist: Aid the patient in quitting.  Help patient develop a quit plan, encourage nicotine replacement therapy or bupropion except in special circumstances, give key advice on successful quitting, and provide supplementary materials.
Strategy 5:

Arrange: Schedule follow-up contact either in person or via telephone.

 

Table 4. Motivational Intervention to Promote Smoking Cessation: “5 R’s”*
Relevance: Encourage patient to indicate why quitting is personally relevant.

Risks: Ask the patient to identify potential negative consequences of tobacco use.

Rewards: Ask the patient to identify potential benefits of stopping tobacco use.

Roadblocks: Ask the patient to identify barriers or impediments to quitting.

Repetition: The motivational intervention should be repeated every time an unmotivated patient has an interaction with a provider.  Tobacco users who have failed in previous attempts should be told that most people make repeated quit attempts before they are successful.

*For detailed recommendations and evidence refer to the VA/DoD Guideline for Management of Tobacco Use.

RATIONALE

Figure 1. Time Course of COPD (Fletcher & Peto, 1977)

Time course of COPD

EVIDENCE STATEMENTS

EVIDENCE TABLE

   

Evidence

Source

 QE

OQ

  SR 

1

Passive smoke exposure increases cough and sputum production.

Leuenberger et al., 1994

I

Good

A

2

Smoking cessation decreases the loss of lung function.

Anthonisen et al.,1994

I

Good

A

3

Smoking cessation decreases mortality.

Anthonisen et al., 2005

I

Good

A

QE = Quality of Evidence; OQ = Overall Quality; SR = Strength of Recommendation (See Appendix A)

Additional resources


3.3 Vaccination

BACKGROUND

Elderly persons and persons of any age with certain chronic medical conditions, including chronic pulmonary conditions, are at increased risk for influenza- or pneumococcal-related complications.  The Advisory Committee on Immunization Practices (ACIP) recommends influenza and pneumococcal vaccination for persons who have chronic disorders of the pulmonary or cardiovascular systems, including asthma (see also VA/DoD endorsement to the U. S. Preventive Services Task Force (USPSTF) guideline on immunization).

ACTION STATEMENT

Provide an annual influenza vaccine to individuals with COPD.  [A]
Provide a pneumococcal polysaccharide vaccine to individuals with COPD.  [B]

RECOMMENDATIONS

  1. An annual influenza vaccination is recommended for individuals with COPD unless contraindicated due to severe anaphylactic hypersensitivity to egg protein.  Only inactivated influenza vaccines should be used. The optimal time to receive influenza vaccine is October - November.  [A]
  2. Although insufficient data exist for use of pneumococcal vaccination in individuals with COPD, data from elderly populations with or without chronic disease provides supportive evidence for its use.  [A]
  3. Pneumococcal vaccines are routinely given as a one-time dose (administer if previous vaccination history is unknown).  One-time revaccinations are recommended 5 years later for people at the highest risk for fatal pneumococcal infection and for people older than 65 years if the first dose was given prior to the age of 65 and more than 5 years have elapsed since the previous dose.  [I]

RATIONALE

EVIDENCE STATEMENTS

3.3.1 Influenza vaccine

Several studies have been conducted in the elderly and high-risk populations as a whole.

3.3.2 Pneumococcal Polysaccharide vaccine (PPV)

The data for pneumococcal vaccination specifically for the COPD population are inconclusive.  Most of the published studies are in the general population and address high-risk patients with chronic disease in general.  Only a few studies have researched the impact of PPV in COPD patients.

EVIDENCE TABLE

    

Evidence

Source

  QE 

OQ

  SR 

1

In the general elderly population, influenza vaccination reduced hospitalization for pneumonia and influenza and all-cause mortality.

Jefferson et al., 2005
Vu et al., 2002

I

Good

A

2

Influenza vaccination decreased COPD exacerbations.

Poole et al., 2006

I

Good

A

3

Influenza vaccination reduced the incidence of outpatient influenza-related acute respiratory illness events, but not influenza-related events leading to hospitalization.

Wongsurakiat et al., 2004

I

Good

A

4

In elderly patients with chronic lung disease, influenza vaccine reduced hospitalizations for pneumonia and influenza and for death.

Nichol et al., 1999a

II-2

Good

B

5

In the general elderly population, pneumococcal vaccine reduces the risk of bacteremia/invasive pneumococcal disease.

Conaty et al., 2004

Cornu et al., 2001

Jackson et al., 2003

I

Good

A

6

In the general elderly population, pneumococcal vaccine does not appear to reduce the risk of all-cause pneumonias.

Jackson et al., 2003

Moore et al., 2000

Watson et al., 2002

I

Fair

C

7

Pneumococcal vaccine reduces the risk of all-cause pneumonias and risk of death due to pneumonia.

Hedlund et al., 2003

Nichol et al., 1999b

Vila-Corcoles et al., 2006

I
I
II-b

Fair

C

8

PPV decreases the rate of pneumonia and mortality due to pneumina in COPD.

Alfageme et al., 2006

I

Good

A

QE = Quality of Evidence; OQ = Overall Quality; SR = Strength of Recommendation (See Appendix A)


Annotation E      Pharmacotherapy Including Bronchodilators and Inhaled Glucocorticoids

4 Therapy Interventions for COPD

4.1 Pharmacotherapy of COPD

BACKGROUND

Pharmacotherapy for patients with COPD should be tailored in steps to achieve the greatest benefit at the lowest level of therapy with the fewest side effects.  Patient preference should also be taken into account when choosing between options which have similar potential benefits and side effects.  The patient should be evaluated periodically until symptom control is optimized.  Consider one to 6 months for each step.  There is no systematic evidence that provides a rationale for what order to use the different pharmacological agents; however, a rationale based upon a consensus of experts advocates a stepped-up approach of treatment of COPD based on the natural history of the disease.

Unless otherwise indicated, when the term therapy is used, it refers to pharmacotherapy with bronchodilators and inhaled glucocorticoids.  At all steps involving therapy, an as-needed short-acting beta 2-agonist is prescribed for acute relief of symptoms (i.e., rescue).  The principles that guide step-care therapy in COPD are as follows: 

  1. There are no pharmacological therapies at present that have shown to modify the rate of decline in pulmonary function or reduce mortality.
  2. Since pharmacological therapies do not modify COPD, the course of therapy is guided by patient symptomatic response, predominantly reduction in dyspnea at rest and exercise, and prevention of future exacerbations.  In the absence of symptoms or exacerbations.  In the absence of symptoms or exacerbations, no pharmacological therapy may be needed.
  3. There are no defined pulmonary function thresholds that provide sufficient guidance to recommend any given bronchodilator therapy over any other for initially treating a patient.  This leads to the concept of starting with single bronchodilator therapy and stepping up rather than starting with the maximal bronchodilator therapy and stepping down.
  4. All bronchodilator therapies can improve symptoms and reduce exacerbations.  Long-acting bronchodilators are more efficacious than short-acting bronchodilators if symptoms persist.
  5. Combination bronchodilator therapy provides the potential of added benefit when single bronchodilator therapy has not achieved sufficient symptomatic improvement.
  6. A slow release theophylline trial has shown to control nighttime respiratory symptoms, but should be used with caution due to potential adverse effects and insomnia.  Theophylline should be discontinued if a symptomatic benefit is not evident within several weeks.
  7. Inhaled glucocorticoids have been documented to improve symptoms and reduce exacerbations predominantly in patients with severe COPD (FEV1 < 50 percent predicted).  Inhaled glucocorticoids are most effective when combined with a long-acting bronchodilator.
  8. Patients should not be prescribed inhaled glucocorticoids before maximal bronchodilator therapy is implemented and has failed to achieve symptomatic control.
  9. Short-acting and long-acting anticholinergics should not be combined.
  10. Patients with COPD have an element of irreversible pulmonary disease and optimal symptomatic control may still leave a patient stable but symptomatic.

Some patients may initially present to be well-controlled on combination therapy that was not documented.  An attempt should be made to carefully step down therapy in such patients to maintain the greatest benefit at the lowest level of therapy with the fewest adverse effects.

See Module C: Pharmacotherapy for specific recommendations and discussion of the supporting evidence.

Table 5. Key Points for Step-up Therapy
Pharmacotherapy for patients with COPD is based on a step-up approach:
  1. Therapy to address symptoms should make use of non-pharmacologic intervention to improve outcomes (i.e., smoking cessation, education, rehabilitation, and pulmonary rehabilitation).
  2. Pharmacotherapy should balance overall efficacy which includes acceptance and adherence against risks for adverse effects (toxicity).
  3. Patient symptomatic responses such as dyspnea, as well as a reduction in exacerbations, should be the primary basis for determining response to therapy.
  4. Continue ongoing evaluation of the patient's response to therapy and progression of disease.
  5. As COPD progresses, additional pharmacotherapy is usually needed.
  6. Patient's preference should be considered to improve acceptance and adherence to therapy.
  7. Patients with severe airflow limitation (FEV1 < 50 percent predicted) and minimal symptoms should be considered for a trial of pharmacologic therapy.
  8. COPD severity based on symptoms and FEV1 should always be documented initially and reassessed periodically based primarily on symptomatic progression of COPD.
  9. The Modified Medical Research Council (MMRC) scale of dyspnea, in addition to clinical assessment, is indicated to grade symptom severity.
  10. Treatment is predominantly based on symptoms and a suggested stepped-up approach is recommended (see Table 6).

Figure 2. Step-Care Pharmacotherapy in COPD
A

Reduce risk factor(s): smoking cessation; influenza and other vaccinations
B

                                     SABA when needed

C

Scheduled SAAC                                   
 OR     +     SABA when needed *     

Combination SAAC + SAAB                          
D

Combination SAAC + LABA                         
OR     +   SABA  when needed *     

LAAC

E

LABA + LAAC + SABA when needed *     
F

Add inhaled glucocorticoids
if repeated exacerbations and FEV1 < 50%

* Theophylline may be added at each step
with caution regarding adverse effects.

SAAC - Short-acting anticholinergic; SABA - Short-acting beta-agonist; LABA - Long-acting inhaled beta-agonist; LAAC - Long-acting anticholinergic
Table 6. Step-Care Pharmacotherapy in COPD
Step Symptoms a Maintenance Therapy b Rescue therapy Other Interventions

A

Asymptomatic

No medication indicated

--

Smoking cessation; influenza, and other vaccinations

B

Symptoms less than daily

No scheduled medication indicated

SABA f

Smoking cessation; influenza, and other vaccinations

C

Symptoms not controlled with rescue therapy or daily symptoms

Scheduled SAAC
or
Combination SABA + SAAC c

SABA f

Smoking cessation; influenza, and other vaccinations

D

Symptoms not controlled b

Combination SAAC + LABA
or
LAAC d

SABA f

Smoking cessation; influenza, and other vaccinations
Consider Pulmonary Rehabilitation g 

E

Symptoms not controlledb

Combination LABA + LAAC d

SABA f

Smoking cessation; influenza, and other vaccinations
Refer to Pulmonary Rehabilitation g 

F

Exacerbations of more than one per year and severe disease (FEV1 < 50%)

Consider adding an inhaled
glucocorticoid e

SABA f

Smoking cessation; influenza, and other vaccinations
Refer to Pulmonary Rehabilitation g 

SAAC- Short-acting anticholinergic; SABA- Short-acting beta-agonist; LABA- Long-acting inhaled beta-agonist; LAAC- Long-acting anticholinergic
      1. Spirometry is essential to confirm the presence of airflow obstruction (low FEV1 and FEV1/VC ratio).  Base therapy on symptoms, but consider alternate diagnoses (heart disease, pulmonary emboli, etc.) if out of proportion to spirometry.
      2. Use the lowest level of therapy that satisfactorily relieves symptoms and maximizes activity level.  Assure compliance and proper use of medications before escalating therapy.  It is unusual for patients with COPD with FEV1 above 70% to require therapy beyond short-acting bronchodilators; if these patients do not improve they should be considered for alternative diagnoses.
      3. Consider use of inhaler containing both a short-acting beta 2-agonist and an anticholinergic.  Nighttime symptoms are frequently better controlled with a long-acting inhaled beta 2-agonist.
      4. Consider adding a theophylline trial (slow release theophylline adjusted to the level of 5 to 12 µg/ml) with caution due to adverse effects.  Nighttime respiratory symptoms are frequently controlled, but theophylline may lead to insomnia.  Discontinue if a benefit is not evident within several weeks.
      5. Consider high dose inhaled glucocorticoids in patients with severe COPD (FEV1 < 50 % predicted) and at least one exacerbation in the prior year.  A combination of a high dose inhaled glucocorticoid and a long-acting beta 2-agonist may help provide long-term maintenance for symptomatic COPD and improve quality of life (QOL).  The use of oral glucocorticoids for maintenance therapy is discouraged.
      6. Short-acting inhaled beta 2-agonists (less than12 puffs/day) may continue to be used as needed.  Inhaled long-acting beta 2-agonists should not be used as rescue therapy.
      7. Pulmonary rehabilitation should be offered to patients who, despite optimal medical therapy, have reduced exercise tolerance and/or dyspnea limiting exercise.

EVIDENCE

Table 7. Effects of Commonly Used Medications on Clinical Outcomes

              OUTCOME

Medication

Improve

Reduce Exacerbation

Other Outcomes

Reduce
Mortality

Adverse Effects

FEV1

Dyspnea

HRQOL

Short-acting beta 2-agonist (SABA)

B

B

NA

B

 

NA

++

Short-acting anticholinergic (SAAC)
 Ipratropium bromide

B

B

B

B

No effect on FEV1 rate of decline

NA

+

Long-acting beta-agonists (LABA)
Formoterol
Slameterol

B

A

A
(Formoterol)
C
(Slameterol)

NA
(Formoterol)
C
(Slameterol)

No effect on FEV1 rate of decline

NA

++

Long-acting anticholinergic
(LAAC)
 Tiotropium

B

A

A

A

Reduce hospitalization
(B)

NA

+

Inhaled glucocorticoids (ICS)
 (in severe patients)

C

B

B

A

No effect on FEV1 rate of decline

NA

++

Theophylline

B

A

B

B

 

NA

+++

Combination
SABA + SAAC

B

B

NA

B

 

NA

++

Combination
SAAC +LABA

B

B

NA

B

 

NA

++

Combination
LAAC +LABA

B

NA

NA

NA

 

NA

++

Combination
LABA +Theophylline

B

B

B

NA

 

NA

+++

Combination
ICS + LABA

B

A

A

A

 

NA

++

The content in each box indicates the strength of recommendation rating for explicit evidence based on RCTs showing positive effect of the drug on clinical outcomes.  A,B,C=see Appendix A; NA=evidence not available; No=no effect; Adverse events: + minimal; ++ some; +++ important.

 

Annotation F      Supplemental and Long-Term Oxygen Therapy

4.2 Oxygen Therapy

BACKGROUND

As COPD progresses, patients often become hypoxic.  These patients may exhibit signs of tissue hypoxia, such as pulmonary hypertension, cor pulmonale, erythrocytosis, edema from right heart failure, or impaired mental status.  Long-term oxygen therapy (LTOT) reverses and prevents hypoxia, and has been shown to improve life expectancy in hypoxemic patients with chronic lung disease.

As COPD progresses, patients often become hypoxemic during exertion and experience a decline in exercise tolerance and performance, as well as an increase in dyspnea.  Patients with advanced COPD, while having normal oxygen saturation during the daytime, may experience desaturation during sleep.  Nocturnal desaturation may cause signs of tissue hypoxia.

ACTION STATEMENT

Patients with COPD should be periodically evaluated for the need of supplemental oxygen.  Supplemental oxygen for those exhibiting signs of tissue hypoxia may increase survival of patients with severe COPD.  Oxygen may also be used for exertional hypoxemia or nocturnal hypoxemia.

RECOMMENDATIONS

  1. Oximetry should be considered in patients with COPD and should be performed in all patients with severe or very severe COPD (FEV1 < 50 percent predicted).  [I]
  2. Evaluation of nocturnal desaturation should be considered in patients with severe or very severe COPD (FEV1 < 50 percent predicted) who exhibit unexplained findings indicating nocturnal hypoxemia (e.g., polycythemia, pulmonary hypertension, and nocturnal restlessness).  [I]
  3. Oxygen therapy should be initiated in patients who have hypoxemia (PaO2 < 55 mm Hg and/or SaO2 < 88 percent).  [A]
  4. Oxygen therapy should be initiated in patients who have hypoxemia (PaO2 of 56 to 59 mm Hg or SaO2 < 89 percent) and signs of tissue hypoxia such as hematocrit above 55, pulmonary hypertension, or cor pulmonale.  [A]
  5. Oxygen therapy should be provided during exercise in stable patients with COPD with exertional hypoxemia (SaO2 < 88 percent).  [B]
  6. Oxygen therapy should be considered for nocturnal hypoxemia (SaO2 < 88 percent).  [I]
  7. Patients who started to receive oxygen therapy while unstable or on suboptimal medical therapy should be reevaluated within one to 3 months for need of long-term oxygen therapy (LTOT).  If repeated evaluation indicates a patient no longer qualifies for oxygen, cessation of oxygen should be considered.  [B]
  8. Patients who continue to receive long-term oxygen therapy (LTOT) should be reevaluated at least annually for continued need of LTOT. [I]
  9. Patients prescribed oxygen should be cautioned about the potentially extreme fire hazard of smoking or lighting cigarettes in the presence of oxygen.  [I]

EVIDENCE STATEMENTS

4.2.1 Long-term oxygen therapy (LTOT)

Mortality is reduced and survival benefits have been shown in patients with chronic hypoxia when long-term oxygen therapy is administered.

4.2.2 Oxygen supplementation during exercise

Exercise tolerance is increased and dyspnea improved in patients with stable COPD with exertional desaturation when they are provided oxygen therapy during exercise.

4.2.3 Evaluation of nocturnal saturation

There are no clear data that patients who have nocturnal desaturation (SaO2 < 90 percent) without evidence of severe daytime hypoxemia (PaO2 ≤ 55 mm Hg) should have nocturnal oxygen therapy. Patients with nocturnal desaturation should be monitored more closely as they are at risk for progression to daytime hypoxia. Reversal of daytime hypoxia is known to result in an increased survival by 6 or more years. Furthermore, there are individuals with mild hypoxia that do not meet criteria for LTOT that may have worsening hypoxia at night. Although treatment of nocturnal hypoxia does not appear to improve survival, there is fairly high progression of nocturnal hypoxia to resting daytime hypoxia which would have survival implications.

EVIDENCE TABLE

     Evidence Source  QE  OQ   R 
1

Patients who have PaO2 < 55mm Hg and/or SaO2 < 88 percent will have mortality benefit with LTOT.

Cranston et al., 2005

NOTT, 1980

 I Good A
2

Oxygen administration slows progression of pulmonary hypertension in hypoxic patients with COPD.

MRC, 1981

NOTT, 1980

Weitzenblum et al., 1985

I Good A
3

Patients with mild to moderate hypoxemia without signs of tissue hypoxia did not demonstrate a survival benefit after 3 years of LTOT.

Gorecka et al., 1997

Cranston et al., 2005

Crockett  et al., 2000

I Good D
4

Oxygen supplementation during exercise improves dyspnea, exercise tolerance, and performance.

Bradley & O’Neill, 2005

Eaton et al., 2002

Fujimoto et al., 2002

Garrod et al., 2000

McDonald et al., 1995

Rooyackers et al., 1997

Stein et al., 1982

I Good A
5

Nocturnal oxygen therapy improves pulmonary hypertension.

Fletcher et al., 1992

 I Good A
6

Nocturnal oxygen therapy does not improve survival.

Chaouat et al., 1999

 I Good A

QE = Quality of Evidence; OQ = Overall Quality; SR = Strength of Recommendation (See Appendix A)

Annotation G     Pulmonary Rehabilitation

4.3 Pulmonary Rehabilitation

BACKGROUND

Despite optimal pharmacological management, patients with COPD frequently have persistent symptoms, reduced exercise tolerance, inability to perform their activities of daily living, and reductions in health and functional status.  Pulmonary rehabilitation complements standard medical therapy and provides additional benefits in these areas.

Pulmonary rehabilitation is a multidisciplinary program of care that comprises a variety of interventions grouped into categories: exercise training, education, and psychological and nutritional counseling.  This therapy may result in significant clinical improvement in multiple outcome areas, including reduction in dyspnea as well as improvements in exercise endurance, muscle strength, health status, and healthcare utilization.  While the individual components have benefits, the greatest efficacy is derived from a comprehensive, integrated program.  Pulmonary rehabilitation should be one part of disease management of symptomatic patients with COPD.  Clear goals should be developed for each patient and communicated to the healthcare team.  Comprehensive programs are delivered by multidisciplinary teams of healthcare professionals.

Table 8. Major Elements of Pulmonary Rehabilitation
Elements of Pulmonary Rehabilitation Anticipated Benefit    R     

Exercise training

Improves exercise endurance and maximal exercise capacity

A

Strength training of upper and lower extremities

Improves strength of upper and lower extremities

A

Psychosocial and educational training

May be beneficial long term to improve QOL and coping with chronic disease, which may reduce utilization of care

B

R = Strength of Recommendation (See Appendix A)

Table 9. Outcomes from Implementing the Elements of Pulmonary Rehabilitation
Outcome

Anticipated Benefit

Quality of Evidence

Dyspnea

Dyspnea reduced

Meta-analysis of RCTs showing substantial benefit

Quality of Life (QOL)

Health-related QOL improved

Meta-analysis of RCTs showing substantial benefit

Healthcare Utilization

Reduced number of hospitalization days

Randomized trials and cohort studies indicating moderate effect

Survival

No effect

Insufficient evidence

ACTION STATEMENT

Pulmonary rehabilitation should be offered to all patients with COPD, who, despite optimal medical therapy, have reduced exercise tolerance and/or dyspnea limiting exercise.  [A]
All patients with COPD with exertional symptoms should be offered a structured program with exercise training to reduce dyspnea and improve exercise tolerance and health-related QOL.  [A]
Pulmonary rehabilitation programs with educational components and self-management training reduce healthcare use.  [B]

RECOMMENDATIONS

Selection of Patients

  1. Pulmonary rehabilitation should be considered for patients with COPD who have dyspnea, reduced exercise tolerance, a restriction in activities, or impaired health status.  [A]
  2. Pulmonary rehabilitation should be offered to all patients who consider themselves disabled by COPD (Level 3 and above on the dyspnea scale).  [B]
  3. Pulmonary rehabilitation is recommended for patients with reduced exercise tolerance and restricted activities because of dyspnea.  [A]

Exercise Training

  1. The exercise program should be supervised and should provide cardiovascular reconditioning with endurance and muscle strength training.  [A]
  2. The initial exercise program should be of sufficient length, duration, and frequency (see Appendix B: Structured Exercise Training Program).  [B]
  3. Endurance training should be performed to improve physical endurance.  [A]
  4. Lower limb strength training should be performed to improve exercise tolerance (walking, cycling); upper extremity training improves arm strength.  [B]
  5. In order to maintain benefits, subsequent exercise training is needed.  [B]
  6. As studies show conflicting results, respiratory muscle training is not recommended to be part of a rehabilitation exercise program.  [B]

Education and Self-Management

  1. Patients with COPD with a prior hospitalization should be referred for pulmonary rehabilitation.  [A]
  2. Educational components and self-management programs should be included in rehabilitation programs, as it can reduce COPD exacerbations, hospital admission, and length of stay.  [B]
  3. Self-management programs should include the following [B]:
    1. Skills training to optimally control the disease
    2. Education about medications and devices and how to use them properly
    3. Instruction on how to deal with exacerbations
    4. Other aspects of coping with the disease.
  4. The benefit of education, psychosocial support, and nutritional therapy as a single intervention, without exercise, are less well-documented.  [I]

RATIONALE

4.3.1 Effect on symptoms of dyspnea

4.3.2 Exercise training

4.3.3 Self-management and education

4.3.4 Psychological-based intervention

4.3.5 Nutrition

EVIDENCE TABLE

   

Evidence

Source

 QE 

OQ

Net Effect

  SR 

1

Significant improvement in dyspnea and COPD QOL (measured by the CRDQ).

ACCP/AACVPR, 1997

Lacasse et al., 2002

I

Good

Substantial

A

2

Significant improvement in dyspnea and exercise capacity for patients with an FEV1 above 35 percent for long-and short-term programs.  Patients with FEV1 below 35 percent required at least 6 months of program.

Salman et al., 2003

I

Good

Substantial

A

3

Rehabilitation improved dyspnea, QOL and exercise capacity.

Kupferberg et al., 2005

Ries et al., 2005

II-2

Fair

Substantial

B

4

Addition of supervised exercise to a dyspnea self-management program that included unsupervised home exercise (walking) led to greater improvement in dyspnea, QOL and exercise capacity.

Carrieri-Kohlman et al., 2005

I

Good

Substantial

A

5

Home-based rehabilitation improved exertional dyspnea (Borg), QOL (CRDQ) and exercise capacity.

Oh, 2003

I

Fair

Moderate

B

Exercise

6

Rehabilitation improves exercise endurance and maximal exercise capacity.

ACCP/AACVPR, 1997
Lacasse et al., 2002

I

Good

Substantial

A

7

Rehabilitation improves peripheral muscle strength.

Troosters et al., 2005

I

Good

Moderate

B

8

Improvements in exercise tolerance are maintained for 6 months to a year.

Bestall et al., 2003

I

Fair

Small

C

9

Respiratory muscle training can improve strength of these muscles, but this does not lead to increased exercise tolerance or better QOL.

 

Lotters et al., 2002
Smith et al., 1992

I

Good

Zero

D

Education and Self-Management

10

Pulmonary rehabilitation program with educational components and structured treatment recommendations for COPD exacerbation reduce healthcare use.

Bourbeau et al., 2003
Gadoury et al., 2005
Gallefoss & Bakke, 2000
Griffiths et al., 2000
Guell et al., 2000
Troosters et al., 2005

I

Fair

Moderate

B

11

Self-management programs (that include education about the medications and how to use them, guide behavior change, and provide emotional support) reduce COPD exacerbations, and hospital admissions, and length of stay.

Bourbeau et al., 2003
Gallefoss & Bakke, 2000
Guell et al., 2000
Monninkhof et al., 2003
Troosters et al., 2005

I

Fair

Moderate

B

QE = Quality of Evidence; Net Effect = Size of Intervention Effect; R = Strength of Recommendation (See Appendix A)


Annotation H     Other Interventions

4.4 Mucolytics, Antioxidants, and Antitussives

BACKGROUND

Patients with COPD often have difficulty with expectoration.  Suppression of an irritating cough may enhance patient comfort, but on the other hand could decrease clearance of secretions.

ACTION STATEMENT

The use of mucolytics, antioxidants, or antitussive medications has little evidence of any effect on lung function.  [D]

RECOMMENDATIONS

  1. N-acetylcysteine (NAC) is not recommended for patients with COPD for the purpose of cough suppression.  [D]
  2. N-acetylcysteine (NAC) 600 mg by mouth every day may be considered to decrease the number of exacerbations in selected patients with COPD with primarily chronic bronchitis who are not on inhaled glucocorticoids.  [B]
  3. Antioxidants, such as alpha-tocopherol (contained in vitamin E preparations) or beta-carotene, should not be administered to patients with COPD, as they have no significant effect on phlegm, cough, or dyspnea.  [D]
  4. Antitussives are not indicated in stable COPD.  [I]

RATIONALE

EVIDENCE STATEMENTS