COPD
Guidelines
Global strategy for the diagnosis, management, and prevention of COPD: GOLD workshop summary. For the most current 2008 version of these influential guidelines go to: http://www.goldcopd.com
ATS / ERS Task Force: Standards for the diagnosis and treatment of patients with COPD: A summary position of the ATS / ERS position paper. For the most recent update of these guidelines go to: http://www.thoracic.org/sections/copd/index.html
Bronchodilators
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
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Impact of inhaled corticosteroids on lung function and exacerbations
Burge PS, Calverley PMA, Jones PW, et al. Randomized, double blind, placebo-controlled study of fluticasone proprionate in patients with moderate to severe COPD: the ISOLIDE 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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The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in COPD. N Engl J Med 2000;343:1902-09. Randomized, controlled study followed over 1000 patients for an average of 4.5 yrs and found no difference in rate of decline in FEV1 in the inhaled steroid group. Patients using triamcinolone had, by some measures, fewer symptoms, but also had a greater rate of decline in bone density that is of unknown clinical significance.
PMID: 11136260
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Impact of combinations of inhaled steroid and long-acting bronchodilators on lung function, exacerbations, and mortality
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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Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. (OPTIMAL Trial) Ann Intern Med 2007; 146:545-555. Year-long Optimal Trial randomized 449 patients with moderate to severe COPD and found addition of salmeterol or salmeterol-fluticasone to tiotropium did not reduce the proportion of patients experiencing an exacerbation, although patients randomized to tiotropium plus salmeterol-fluticasone had fewer admits for COPD (31 vs. 18%, p = .01). Of note, 45% of patients randomized to tiotropium alone or tiotropium-salmeterol did not complete the study compared to 26% receiving tiotropium plus salmeterol-fluticasone (p < .001).
PMID: 17310045
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Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. (UPLIFT Trial) N Engl J Med 2008; 359:1543-54. The UPLIFT study added tiotropium or placebo to 5,993 COPD patients’ baseline regimen. Nearly half were already on a combination inhaled corticosteroid/long-acting B-agonist and over 70% were on an inhaled steroid or long-acting B-agonist. Unlike the Aaron study above, addition of tiotropium reduced exacerbations (median delay to first exacerbation of 16.7 months vs. 12.5 months for placebo), but did not affect the rate of decline in FEV1. In contrast to the findings of a recent meta-analysis (Singh S et al. JAMA 2008;300:1439), tiotropium was not associated with increased risk of cardiovascular morbidity or mortality.
PMID: 18836213
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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. 2-year INSPRIRE 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
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Decramer M, Celli B, Kesten S, et al. Effect of tiotropium on outcomes in patients with moderate COPD (UPLIFT): a prespecified subgroup analysis of a randomized controlled trial. Lancet 2009;374:1171-8. This study is generating interest in more intensive treatment of patients with less severe COPD, although arguably the clinical benefits were modest. Among 2,739 patients from UPLIFT with moderate COPD (post-bronchodilator FEV1 = 50 – 70% predicted), the rate of decline in post-bronchodilator FEV1 with tiotropium was 43 mL/yr vs. 49 mL/yr with placebo (p = .024). The mean exacerbation rate was 0.56/year with tiotropium vs. 0.70/year with placebo (p < 0.0001). Patients were recruited from pulmonary clinics and may have been more symptomatic than average COPD patients with comparable severity of obstruction.
PMID: 19716598
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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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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
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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
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Case management
Rice KL, Dewan N, Bloomfield HE, et al. Disease management program for chronic obstructive pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med 2010;182:890-6. The relatively simple provision of a 1- to 1.5-hour information session, individual action plan with home courses of antibiotics and prednisone, and a case manager led to a marked reduction in hospitalizations and ED visits, with a NNT of 3 to prevent one event per patient-year.
PMID: 20075385
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 the above 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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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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