COPD


























  • Reference [2,5]
Spirometry findings in COPD
Severity FEV1/FVC
(post-bronchodilator)
FEV1
(% predicted post-bronchodilator)
Mild COPD
(GOLD 1)
≤ 0.7 ≥ 80%
Moderate COPD
(GOLD 2)
≤ 0.7 50 - 80%
Severe COPD
(GOLD 3)
≤ 0.7 30 - 50%
Very Severe COPD
(GOLD 4)
≤ 0.7 < 30%





  • Reference [1]
2011 ACP / ATS / ACCP / ERS maintenance recommendations
All patients
  • SABA +/- SAMA as needed
  • Tobacco cessation if smoker
Stable patients with FEV1 60 - 80% of predicted
  • SABA +/- SAMA as needed
  • LABA or LAMA may be used
Stable patients with FEV1 < 60% of predicted
  • SABA +/- SAMA as needed
  • LABA or LAMA
  • Combination therapy (LABA +/- LAMA +/- ICS) may be used in some patients
Stable patients with FEV1 < 50% of predicted
  • SABA +/- SAMA as needed
  • LABA or LAMA
  • Combination therapy (LABA +/- LAMA +/- ICS) may be used in some patients
  • Pulmonary rehabilitation (exercise therapy, smoking cessation, etc.)
Indications for continuous oxygen therapy
  • COPD patients with resting hypoxemia of PaO2 ≤ 55 mmHg or SpO2 ≤ 88%
  • Physiologic indications for the use of long-term oxygen therapy include cor pulmonale or polycythemia with PaO2 between 55 and 59 mmHg
  • The therapeutic goal is to maintain SpO2 > 90% during rest, sleep, and exertion [1,2]
  • See oxygen measurements below

  • Reference [5]
2017 GOLD maintenance recommendations
Step 1 - Assign patient a group
  • Symptom score
  • Exacerbation history within past year
    • Mild: None or one that did not require hospitalization
    • Moderate/severe: ≥ 2 exacerbations or ≥ 1 that required hospitalization
GROUP A: mMRC 0 - 1 or CAT < 10 and mild exacerbation history
  • SABA or SAMA as needed
GROUP B: mMRC ≥ 2 or CAT ≥ 10 and mild exacerbation history
  • SABA or SAMA as needed
  • LAMA or LABA
  • If necessary, progress to LAMA + LABA
GROUP C: mMRC 0 - 1 or CAT < 10 and moderate/severe exacerbation history
  • SABA or SAMA as needed
  • LAMA
  • If necessary, progress to LAMA + LABA (preferred) or LABA + ICS
GROUP D: mMRC ≥ 2 or CAT ≥ 10 and moderate/severe exacerbation history
  • SABA or SAMA as needed
  • LAMA
  • If necessary, progress to LAMA + LABA (preferred) or LABA + ICS
  • If still uncontrolled, progress to LAMA + LABA + ICS (triple therapy)
  • For patients who are uncontrolled on triple therapy, consider the following:
    • Consider roflumilast if FEV1 < 50% of predicted and patients has chronic bronchitis
    • Consider macrolide in former smokers
Indications for continuous oxygen therapy
  • COPD patients with resting hypoxemia of PaO2 ≤ 55 mmHg or SpO2 ≤ 88% with or without hypercapnia confirmed twice over a 3-week period; OR
  • PaO2 between 55 mmHg and 60 mmHg or SpO2 of 88% if there is evidence of pulmonary hypertension, peripheral edema suggesting congestive heart failure, or polycythaemia (hematocrit > 55%)
  • See oxygen measurements below

  • Reference [2,5]
ATS / GOLD recommendations for acute exacerbations
Bronchodilators
  • SABA +/- SAMA via MDI with spacer or hand-held nebulizer as needed
  • Add LABA or LAMA and continue as maintenance therapy if not already using
Corticosteroids
  • Prednisone 40 mg a day for 5 - 7 days
  • NOTE: A recent study found that prednisone 40 mg a day for 5 days was noninferior to prednisone 40 mg a day for 14 days (see steroid studies)
  • Consider using an inhaled corticosteroid
Antibiotics
  • May be initiated in patients with increase in dyspnea, increase in sputum production/purulence, and/or those who require mechanical ventilation
  • Choice should be based on local bacterial resistance patterns. Typical choices include amoxicillin, doxycycline, macrolides, or cephalosporins (cefpodoxime, cefprozil, cefuroxime, cefdinir). Duration of therapy should be 5 - 7 days.
  • In patients who have failed prior antibiotic therapy, consider amoxicillin/clavulanate or a respiratory fluoroquinolones (gatifloxacin, levofloxacin, moxifloxacin)
Studies
  • In studies, the effects of antibiotics on acute COPD exacerbations have been mixed. A Cochrane meta-analysis published in 2018 looked at the issue and found that "antibiotics have some effect on inpatients and outpatients, but these effects are small, and they are inconsistent for some outcomes (treatment failure) and absent for other outcomes (mortality, length of hospital stay)." [PMID 30371937]
Oxygen
  • Oxygen as needed to maintain SpO2 between 88 - 92% [2,5]






  • Reference [4]
Normal ABG values
Measure Normal range
pH 7.3 - 7.5
PaO2 ≥ 80 mmHg
PaCO2 30 - 50 mmHg
HCO3 21 - 27 mEq/L
SaO2 ≥ 95%


  • Reference [4]
Relation between PaO2 and SaO2
Degree of hypoxemia PaO2 SaO2
Normal ≥ 80 mmHg 95 - 100%
Mild 60 - 79 mmHg 90 - 94%
Moderate 40 - 59 mmHg 75 - 89%
Severe < 40 mmHg < 75%




LAMA vs other studies

LAMA vs Placebo in Early COPD, NEJM (2017) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=841 | length = 24 months) in patients with mild-to-moderate COPD
  • Treatment: Tiotropium 18 mcg once daily vs Placebo
  • Primary outcome: Between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV1) before bronchodilator use
  • Results:
    • The FEV1 in patients who received tiotropium was higher than in those who received placebo throughout the trial (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use; p<0.001 for all comparisons)
  • Findings: Tiotropium resulted in a higher FEV1 than placebo at 24 months and ameliorated the annual decline in the FEV1 after bronchodilator use in patients with COPD of GOLD stage 1 or 2

LAMA vs Placebo in Advanced COPD, NEJM (2008) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=5993 | length = 4 years) in patients with moderate-to-severe COPD
  • Treatment: Tiotropium 18 mcg once daily vs Placebo. All other respiratory meds except for other inhaled antimuscarinics were permitted.
  • Primary outcome: Rate of decline in the mean FEV1 before and after bronchodilation beginning on day 30
  • Results:
    • Mean absolute improvements in FEV1 in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation), as compared with the placebo group (p<0.001).
    • After day 30, the differences between the two groups in the rate of decline in the mean FEV1 before and after bronchodilation were not significant
  • Findings: In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV1

FLAME Study - Indacaterol–Glycopyrronium vs Salmeterol–Fluticasone for COPD, NEJM (2016) [PubMed abstract]
  • The FLAME study enrolled 3362 patients with COPD
Main inclusion criteria
  • COPD with ≥ 1 exacerbation in last year
  • Smoking history of ≥ 10 pack-years
  • Post-bronchodilator FEV₁ 25% - 60% of predicted value
  • Post-bronchodilator FEV₁/FVC < 0.70
Main exclusion criteria
  • Long QT syndrome or QTc > 450 ms
  • Narrow-angle glaucoma
  • Symptomatic benign prostatic hyperplasia
  • Requiring O₂ therapy for > 12 hours a day
Baseline characteristics
  • Average age 64 years
  • Average duration of COPD - 7.3 years
  • Using inhaled glucocorticoids - 56%
  • Current smoker - 40%
  • Average post-bronchodilator FEV₁ % of predicted - 44%
  • Average post-bronchodilator FEV₁/FVC - 0.416
Randomized treatment groups
  • Group 1 (1680 patients) - Indacaterol 110 μg + glycopyrronium 50 μg once daily for 52 weeks
  • Group 2 (1682 patients) - Salmeterol 50 μg + fluticasone 500 μg twice daily for 52 weeks
  • Before the treatment phase, patients were entered into a 4-week run-in period with tiotropium only. After the run-in phase, patients were randomized to study treatment and all other preventative inhalers were prohibited. Open-label salbutamol (100 μg) was provided as rescue medication.
  • Treatment was given as double dummy inhalers
Primary outcome: Annual rate of all COPD exacerbations (mild, moderate, or severe). COPD exacerbations were defined as mild (involving worsening of symptoms for > 2 consecutive days but not leading to treatment with systemic glucocorticoids or antibiotics), moderate (leading to treatment with systemic glucocorticoids, antibiotics, or both), or severe (leading to hospital admission or a visit to the emergency department that lasted > 24 hours in addition to treatment with systemic glucocorticoids, antibiotics, or both).
Results

Duration: 52 weeks
Outcome LABA/LAMA LABA/ICS Comparisons
Primary outcome (annual rate of exacerbations) 3.59 4.09 Rate ratio 0.88, 95%CI [0.82 - 0.94], p<0.001
Median time to first exacerbation 71 days 51 days HR 0.84, 95%CI [0.78 - 0.91]. p<0.001
Annual rate of moderate or severe exacerbations 0.98 1.19 HR 0.83, 95%CI [0.75 - 0.91]. p<0.001
Pneumonia 3.2% 4.8% p=0.02
Oral candidiasis 1.2% 4.2% N/A
  • The standardized area under the curve for FEV₁ from 0 to 12 hours was measured in a subgroup of 556 patients; the change from baseline was significantly greater in Group 1 than in Group 2, with a between-group difference of 110 ml at week 52 (P<0.001)
  • The median percentage change over a period of 52 weeks in the ratio of 24-hour urinary cortisol to creatinine was +5.62% in Group 1 and –10.39% in Group 2
  • In a subgroup analysis, indacaterol–glycopyrronium was superior to salmeterol–fluticasone regardless of baseline eosinophil count (< 2% vs > 2%)

Findings: Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year
StraightHealthcare analysis
  • The FLAME study found that the addition of an inhaled anticholinergic was more effective than an inhaled corticosteroid in patients with COPD who were receiving a long-acting beta agonist
  • Anticholinergics were superior across a broad array of outcome measures. They also carried a significantly lower risk of pneumonia.

LABA VS ICS

LABA/ICS vs LABA vs ICS vs Placebo in patients with COPD, NEJM (2007) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=6112 | length = 3 years) in patients with COPD
  • Treatment: Salmeterol/Fluticasone 50/500 twice daily vs Salmeterol 50 twice daily vs Fluticasone 500 twice daily vs Placebo
  • Primary outcome: The primary outcome was death from any cause over three years of follow-up
  • Results:
    • Primary outcome: Salmeterol/Fluticasone - 12.6%, Salmeterol - 13.5%, Fluticasone - 16%, Placebo - 15.2%
    • All comparisons were nonsignificant except for Salmeterol/Fluticasone vs Fluticasone (p=0.007)
  • Findings: The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients.

Supplemental Oxygen vs None in COPD with Moderate Desaturation, NEJM (2016) [PubMed abstract]
  • A study published in the NEJM enrolled 738 patients with COPD and moderate desaturations at rest or during exercise
Main inclusion criteria
  • Stable COPD
  • Resting desaturation (SpO2 89 - 93%) or exercise-induced desaturation (during the 6-minute walk test, SpO2 ≥ 80% for ≥ 5 minutes and < 90% for ≥ 10 seconds)
  • ≥ 10 pack-year smoking history
  • Postbronchodilator FEV1/FVC < 0.70 and postbronchodilator FEV1 < 70% of predicted or > 70% of predicted and radiologic evidence of emphysema
Main exclusion criteria
  • Hospitalization or COPD exacerbation within last 30 days
  • Desaturation below 80% for at least 1 minute during the 6-minute walk
Baseline characteristics
  • Average age 69 years
  • Qualifying criteria: Resting desat - 18% | Exercise desat - 43% | Both - 39%
  • Average resting SpO2 on room air - 93%
  • Average postbronchodilator FEV1 (% predicted) - 46%
  • Average postbronchodilator FEV1/FVC - 0.46
  • Using home oxygen at enrollment - 16%
  • Current smoker - 27%
Randomized treatment groups
  • Group 1 (370 patients) - No supplemental oxygen
  • Group 2 (368 patients) - Supplemental oxygen
  • In the supplemental oxygen group, patients were prescribed 24-hour oxygen if their resting SpO2 was 89 - 93%. If patients only had desaturations during exercise, they were prescribed oxygen during sleep and exercise. Oxygen was prescribed at 2 L/min at rest and adjusted to keep sats ≥ 90% for at least 2 minutes during ambulation.
  • In the no supplement group, oxygen was only given if resting sats decreased to ≤ 88% or if exercise-induced desats of < 80% occurred for ≥ 1 minute. Oxygen was prescribed for 1 month and then reassessed.
  • Patients using oxygen at enrollment had to agree to stop if randomized to the no supplement group
Primary outcome: Composite of overall mortality or first hospitalization for any cause
Results

Duration: Median of 18.4 months
Outcome No oxygen Oxygen Comparisons
Primary outcome (annual rate) 36.4% 34.2% HR 0.94, 95%CI [0.79 - 1.12], p=0.52
Overall mortality (annual rate) 5.7% 5.2% HR 0.90, 95%CI [0.64 - 1.25], p=0.53
First hospitalization for any cause (annual rate) 34.5% 31.6% HR 0.92, 95%CI [0.77 - 1.10], p=0.37
Average oxygen use per day 1.8 hours 13.6 hours N/A
  • There was no significant difference between groups for COPD-related hospitalizations (rate ratio 0.99, 95%CI [0.83 - 1.17]), and COPD exacerbations (rate ratio 1.08, 95%CI [0.98 - 1.19])
  • There was no significant difference between groups in measures of quality of life and lung function
  • In Group 2, 23 patients reported tripping/falling over equipment and 5 patients reported fires or burns

Findings: In patients with stable COPD and resting or exercise-induced moderate desaturation, the prescription of long-term supplemental oxygen did not result in a longer time to death or first hospitalization than no long-term supplemental oxygen, nor did it provide sustained benefit with regard to any of the other measured outcomes

Azithromycin vs Placebo for Prevention of COPD Exacerbations, NEJM (2011) [PubMed abstract]
  • A study in the NEJM enrolled 1142 patients with COPD
Main inclusion criteria
  • Diagnosis of COPD
  • ≥ 10 pack-years smoking history
  • PFTs consistent with COPD
  • Using oxygen or had received steroids within one year
  • Been to ER or hospitalized for COPD
Main exclusion criteria
  • Asthma
  • Resting heart rate > 100 bpm
  • A prolonged QT interval or using medications that prolong the QT interval
  • Hearing impairment
Baseline characteristics
  • Average age 65 years
  • Average % of predicted FEV1 - 39
  • Average pack-year smoking history - 58
  • Current smoker - 22%
  • Using ICS + LAMA + LABA - 48%
  • Long-term oxygen therapy - 60%
Randomized treatment groups
  • Group 1 (558 patients) - Azithromycin 250 mg once daily for 1 year
  • Group 2 (559 patients) - Placebo once daily for 1 year
Primary outcome: time to the first acute exacerbation of COPD, defined as “a complex of respiratory symptoms (increased or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids"
Results

Duration: 1 year
Outcome Azithromycin Placebo Comparisons
Primary outcome (median time to first exacerbation) 266 days 174 days p<0.001
Frequency of exacerbations (# per patient-years 1.48 1.83 p=0.01
Decrease in hearing 25% 20% p=0.04
Hospitalization related to COPD (mean events/patient-year) 0.34 0.49 p=0.14

Findings: Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known.

Prednisone for 5 days vs 14 days in Acute COPD Exacerbation, JAMA (2013) [PMID 23695200]
  • Design: Randomized, placebo-controlled trial (N=311, length=180 days)
  • Treatment: Prednisone 40 mg once daily for 5 vs 14 days
  • Primary outcome: time to next exacerbation within 180 days
  • Results:
    • Patients with reexacerbation within 180 days: 5 days - 36%, 14 days - 37% (p=0.006 for noninferiority)
    • Median time to reexacerbation: 5 days - 43.5 days, 14 days - 29 days
  • Findings: In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD.