Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease (2020 Report).

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Inhaled Monotherapy

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 multicenter 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, double-blind, double-dummy trial, over 7000 patients with at least one exacerbation over the previous year were randomized to receive either tiotropium or salmeterol for one year. They continued on baseline therapies, including corticosteroids, except anticholinergic and long-acting β2-agonists were discontinued. The primary endpoint of first exacerbation was increased by 42 days in the tiotropium group (p<0.001). This study suggests anticholinergic therapy may be the better 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, 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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Chapman KR, Hurst JR, Frent SM et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): A randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med. 2018;198:329-339. This study compared de-escalation to LABA/LAMA vs. continued triple therapy in  patients with moderate-to-severe COPD and infrequent exacerbations. Direct de-escalation to LABA/LAMA led to a small decrease in lung function (26 mL), with no difference in exacerbations. Of note, a subgroup of patients with eosinophil counts >300 at baseline had greater lung function loss and higher exacerbation risk.

PMID: 29779416

Lipson DA, Barnhart F, Brealey N et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018; 378:1671-1680. The IMPACT trial randomized over 10.000 subjects to triple therapy (ICS/LAMA/LABA) or dual therapy (LABA/ICS or LABA/LAMA). In contrast to the aforementioned Wisdom, Impact, and Sunset trials, triple therapy resulted in fewer exacerbations (0.91/year) compared to LABA/ICS (1.07/year), which in turn was superior to LABA/LAMA (1.21/year).  A critique of the trial is that patients with a history of asthma were not excluded and most patients randomized to dual therapy were on an ICS prior to enrollment, raising the possibility that abrupt withdrawal of ICS accounted for the difference in efficacy.

PMID: 29668352

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Papi A, Vestbo J, Fabbri L et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet. 2018; 391:1076-1084. This year-long trial compared triple therapy to LABA/LAMA among 1,500 patients with severe, symptomatic COPD and found triple therapy had lower rates of moderate to severe exacerbations (0.5/year) as compared to LABA/LAMA group (0.59/year, p = .04) - several years of treatment to prevent 1 exacerbation. The benefit of triple therapy was more pronounced in patients with a chronic bronchitis phenotype or with > 2% eosinophils at baseline.

PMID: 29429593

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

Butler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. N Engl J Med. 2019; 381:111-120. RCT of 653 patients with acute exacerbation of COPD during a primary care clinic visit were assigned to usual care guided by CRP point of care testing vs usual care alone. Fewer patients in CRP-guided group reported antibiotic use than in usual care group (57% vs 77%, adjusted OR 0.31) without any difference in COPD related health status (as measured by Clinical COPD Questionnaire). The lack of widely available POC CRP testing in the United States may limit applicability.

PMID: 31291514

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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 a 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

Flandes J, Soto FJ, Cordovilla R et al. Bronchoscopic lung volume reduction. Clin Chest Med. 2018 ;39:169-180. Comprehensive review of bronchoscopic lung volume reduction with an emphasis on recently FDA approved unidirectional endobronchial valves.

PMID: 29433712

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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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