ATS Reading List

COPD

Guidelines

Global strategy for the diagnosis, management, and prevention of COPD: GOLD workshop summary (2015).
PMID 11316667
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Inhaled Monotherapy

Burge PS, Calverley PMA, Jones PW, et al. Randomized, double blind, placebo-controlled study of fluticasone propionate in patients with moderate to severe COPD: the ISOLDE trial. BMJ 2000; 320:1297-1303. Use of inhaled steroid did not improve the rate of decline in FEV1 compared to placebo. The fluticasone group had a median of 0.99 exacerbations/yr vs. 1.32/yr in the placebo arm. Response to oral steroids given in the run-in phase was not predictive of subsequent benefit from inhaled steroid.
PMID: 10807619
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Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator. Ann Intern Med 2005;143:317-26. A large multi-center RCT of VA patients with moderate to severe COPD (mean baseline FEV1 36%) found tiotropium reduced the proportion of patients with 1 or more exacerbations during 6 months of treatment vs. placebo (27.9 % vs. 32.3 %). These results support using tiotropium in COPD patients with moderate to severe obstruction and frequent exacerbations
PMID: 16144890

Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093-103. In a prospective, randomized, double-blind, double-dummy trial, over 7000 patients who had had at least one exacerbation over the previous year were randomized to receive either tiotropium or salmeterol for one year. They continued on their other therapies, including corticosteroids, but any prescribed anticholinergic or long-acting β2-agonist was discontinued. The primary endpoint of first exacerbation of COPD was increased by 42 days in the tiotropium group (p<0.001). This study offers some evidence that perhaps anticholinergic therapy would be more appropriate as initial long-acting bronchodilator therapy.
PMID: 21428765
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Inhaled Combination Therapy

Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775-89. The TORCH study randomized over 6,000 patients with baseline FEV1 < 60% predicted to placebo vs. salmeterol alone vs. fluticasone alone vs. a combination of salmeterol and fluticasone over 3 years. Compared to placebo, patients receiving combination therapy had a 0.9% annual reduction in mortality (p = .052). Use of salmeterol, fluticasone, or a combination of the 2 reduced the frequency of exacerbations, but p was >.10 for all 3 for reducing risk of COPD-related death. All-cause mortality and COPD-related death were lower with combination therapy than fluticasone alone (p = .007 and .008, respectively).
PMID: 17314337
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Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. (INSPIRE Trial) Am J Respir Crit Care Med 2008; 177:19-26. The 2-year INSPIRE study randomized 1,323 patients with mean baseline FEV1 39% predicted to the above arms and found no difference in exacerbation rate, but also had a higher proportion of patients randomized to tiotropium withdraw from the study (42 vs. 34% in the salmeterol-fluticasone group, p = .005). Although a greater proportion of patients receiving salmeterol-fluticasone had pneumonia (8 vs. 4%), this group had lower all-cause mortality (3 vs. 6%, p = .03). However, this mortality benefit may be attributable to incomplete follow-up of patients who withdrew from the study.
PMID: 17916806

Wedzicha JA, Banerji D, Chapman KR,et al, FLAME Investigators. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med 2016; 374: 2222-2234. The FLAME trial randomized 3300 patients with COPD and high exacerbation risk to indacaterol–glycopyrronium once daily versus salmeterol–fluticasone twice daily and found the LAMA/LABA combination reduced the annual exacerbate rate by 11% compared to using an ICS/LABA inhaler. Additionally, the salmeterol-fluticasone group had a higher rate of pneumonia (4.8 vs 3.2%).
PMID: 27181606
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Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014; 371:1285-94. The WISDOM trial randomized 2,485 patients with severe or very severe COPD and an exacerbation within the preceding year to either triple therapy with tiotropium, serevent, and high-dose fluticasone or continued long-acting bronchodilators with stepwise withdrawal of fluticasone over 3 months. After 1 year of follow-up, there was no significant difference in time to first moderate or severe exacerbation. There were no clinically-significant changes in dyspnea or health status between groups. Mean FEV1 was 38 ml higher in the triple therapy group.
PMID: 25196117
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Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β 2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet. 2016; 388:963-73. This randomized blinded trial compared beclomethasone/formoterol vs beclomethasone/formoterol/glycopyrronium in 1360 patients with severe or very severe COPD. They found a small but significant improvement in their primary endpoints of pre- (80 mL) and post-dose (120 mL) FEV1, but no change in dyspnea score at 26 weeks. There was a small 0.12/year decrease in moderate to severe exacerbations.
PMID: 27598678

Phosphodiesterase-4 inhibitors

Martinez, Fernando J., Calverley PM, Goehring UM, et al. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015; 385:857-866. This is the first large trial to study the addition of roflumilast to inhaled corticosteroids and long-acting beta-agonists in patients with severe COPD and symptoms of chronic bronchitis. A majority of the 1,945 patients (70%) were also on tiotropium. They found a 14.2% decrease in rate of moderate to severe exacerbations over the course of 1 year in the intervention group. Of note, the study population was limited to those with a chronic bronchitic phenotype, and side effects were common.
PMID: 25684586

Azithromycin to prevent COPD exacerbation

Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689-98. In a large study of patients who required continuous oxygen or had required systemic steroids in the last year and had had at least one prior exacerbation, but who were stable for at least a month prior to the study, the use of daily azithromycin was found to increase the time to subsequent exacerbation from six months to nine months. An audiology-confirmed hearing decrement occurred in 25% of study patients and 20% of placebo patients (p=0.04).
PMID: 21864166
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Systemic corticosteroids in exacerbations

Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of COPD. N Engl J Med 1999;340:1941-7. Multicenter, double blind, placebo- controlled study found modest benefit to use of high-dose intravenous steroids. Steroid group had fewer treatment failures (combined endpoint of death, need for intubation, readmission, or intensification of pharmacologic therapy), and shorter hospital stays, but the primary benefit was in decreasing the need to intensify therapy with use of open-label steroids. No benefit from steroids was present at 6 months of f/u, and 2 week and 8 week courses were equally effective.
PMID: 10379017
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Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013; 309:2223-31. When compared with a 14 day systemic glucocorticoid course, 5 days was non-inferior in 6 month re-exacerbation rate. Patients in the 5 day treatment group received a lower cumulative dose of glucocorticoids during the trial, but there was no difference in glucocorticoid related adverse effects.
PMID: 23695200
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Role of antibiotics in exacerbations

Anthonisen NR, Manfreda J, Warren CPW et al. Antibiotic therapy in exacerbations of COPD. Ann Intern Med 1987;106:196-204. Famous study often cited by proponents of antibiotic use for COPD exacerbations. Randomized, blinded, controlled study found use of antibiotics in the presence of increased dyspnea, increased sputum production, and increased sputum purulence improved outcomes. The improvement was no longer significant, however, after controlling for use of oral steroids.
PMID: 3492164

Daniels JM, Snijders D, de Graaff CS, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;181:150-7. This study attempts to address the perennial question of the utility of antibiotics in acute COPD exacerbations. In an RCT of 265 exacerbations that excluded patients with fever and radiographic infiltrates, the addition of 7 days of doxycycline to prednisone did not lead to a significant improvement in 30-day clinical response, which was the primary endpoint, though secondary outcomes of clinical cure and clinical success at day 10 were improved in the antibiotic arm. The negative findings with respect to the primary endpoint challenge the reflex use of antibiotics in this setting, though the exclusion of severe exacerbations, patients with objective evidence of infection, and concern about doxycycline resistance leave unanswered the question of when antibiotics are truly indicated.
PMID: 19875685

Supplemental oxygen

NOTT group. Continuous or nocturnal oxygen therapy in hypoxemic COPD. Ann Intern Med 1980;93: 391-8. Famous multicenter study showing use of continuous oxygen therapy (>17 hr/d) resulted in lower mortality than use of nocturnal therapy (12 hr/d) in pts. with PaO2 55 mmHg or PaO2 59 mmHg and pulmonary hypertension, right-sided failure, or Hct > 55%.
PMID: 6776858

MRC Working Party. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981;8222:681-5. Another well known study showing improved survival with continuous oxygen in hypoxemic COPD patients.
PMID: 6110912

Long-Term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med 2016; 375: 1617-1627. This multicenter trial randomized 220 patients with resting oxygen saturation 89 to 93% to 24 hours/day supplemental oxygen plus 148 patients with exercise-induced hypoxia (O2 sat 80 - 89% with exertion) to supplemental oxygen during exercise and sleep only and compared these groups to 379 patients randomized to no treatment. They found no difference in time to death, first hospitalization, nor any other outcomes over 1 to 6 years of observation. Of note, the study was powered to detect at 40% mortality difference, an effect matched by few medical interventions. Nonetheless, this study supports limiting supplemental oxygen primarily to COPD patients with severe resting hypoxemia.
PMID: 27783918
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Lung volume reduction surgery

NETT Research Group. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med 2001;345:1075-83. Early results from NETT found a 16% 30-day mortality following LVRS in the 69 patients with FEV1 < 20% predicted AND homogenous disease per CT OR DLCO < 20% predicted. This population had higher overall mortality than comparable patients randomized to medical treatment. Survivors of LVRS had modest improvements in exercise tolerance and FEV1, but similar measures of quality of life.
PMID: 11596586
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Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema: NETT Research Group. N Engl J Med 2003;348:2059-73. After excluding the 140 pts identified as having high risk of mortality based on an interim analysis, a greater proportion of LVRS patients had improved exercise tolerance compared to the medical therapy arm (16% vs. 3%), but there was no survival advantage after 24 months. Subgroup analysis found patients with predominantly upper lobe disease and low exercise capacity had improved mortality, while patients with non-upper lobe emphysema and high exercise capacity had higher mortality following LVRS compared to medical therapy.
PMID: 12759479
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Pulmonary Rehabilitation

Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013; e13-e64.

This guideline replaces the 2006 version, provides an updated definition of pulmonary rehabilitation, and highlights new data demonstrating the efficacy of pulmonary rehab in patients with COPD. It also addresses the use of pulmonary rehabilitation in other pulmonary diseases.
PMID: 24127811
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Asthma-COPD Overlap Syndrome

Postma DS, Rabe KF. The asthma–COPD overlap syndrome. New Engl J Med. 2015; 373:1241-9. Efforts to define patients with asthma-COPD overlap syndrome (ACOS) have generated confusion and controversy. In this review, the authors note that although debate is long-standing, current data do not support the designation of ACOS as a "disease entity". They recommend continued efforts to define ACOS including determining treatment response, and emphasized complete and objective documentation of these patients while generating observational data.
PMID: 26398072

Survival

Traver GA, Cline MG, Burrows B. Predictors of mortality in COPD: A 15-year f/u study. Amer Rev Res Dis 1979;119:895-902. Ubiquitously cited study looking at FEV1 and survival. After controlling for age, the FEV1 after bronchodilator was the best predictor of survival, but was less predictive in patients over 65. The observed wide variability in survival of individual patients with similar initial FEV1 values has important implications for patients considering surgical treatments for their COPD.
PMID: 453709

Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004;350:1005-12. This study found a combination of BMI, FEV1, modified MRC dyspnea scale, and 6 minute walk (i.e. the BODE index) was a better predictor of mortality than FEV1 alone. The BODE index may prove to be a better guide than FEV1 for assessing the efficacy of new treatments and adjusting the aggressiveness of therapy.
PMID: 14999112
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Last Reviewed: June 2017