COPD

Overview
Pauwels RA, Buist AS, Calverley PMA et al. Global strategy for the diagnosis, management, and prevention of COPD: GOLD workshop summary. Am J Respir Crit Care Med 2001; 163:1256-76. Supported by the NHLBI and WHO and endorsed by the ATS.  For the most current version of these guidelines go to: http://www.goldcopd.com  Original print version is at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11316667

Klaus F. Rabe, Suzanne Hurd, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: GOLD Executive Summary.  Am. J. Respir. Crit. Care Med. 2007. 176: 532-555.  Updated consensus guildelines for the diagnosis, management and prevention of COPD. http://ajrccm.atsjournals.org/cgi/content/full/176/6/532?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&titleabstract=gold+copd&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

ATS / ERS Task Force: Standards for the diagnosis and treatment of patients with COPD: A summary position of the ATS / ERS position paper. Eur Respir J 2004;23:932-46.  This is an abbreviated summary of a serially updated web document: http://www.thoracic.org/sections/copd/index.html   Original print version is at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15219010

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16144890

Inhaled steroids and risk of non-vertebral fracture
The following are two examples of recent studies indicating the risk of fracture is increased primarily in the setting of high-dose ICS use.
Lee TA, Weiss KB. Fracture risk associated with inhaled corticosteroid use in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;169:855-9. This nested case-control study in the VA population found current use of high dose inhaled corticosteroids (>700ug/day of beclomethasone equivalent) was associated with increased risk of nonvertebral fractures (adjusted OR 1.68). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14711795

Suissa S, Baltzan M, Kremer R, et al. Inhaled and nasal corticosteroid use and the risk of fracture. Am J Respir Crit Care Med 2004;169:83-8.  Population-based nested case-control study found the overall risk of any type of non-vertebral fracture with current ICS use was not elevated.  The rate of upper-extremity fracture increased by 12% with each 1000 mcg increment in daily ICS dose.  The risk of hip fracture among patients followed for 8 years increased only with daily doses greater than 2,000 mcg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14551165&query_hl=25

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 Flovent 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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10807619

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11136260
   
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 much-anticipated 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). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17314337&query_hl=1&itool=pubmed_docsum

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. Ann Intern Med  2007; 146:545-555.  Year-long RCT of 449 patients with moderate to severe COPD 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).  http://www.ncbi.nlm.nih.gov/pubmed/17310045?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.  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).  http://www.ncbi.nlm.nih.gov/pubmed/17916806?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10379017

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3492164

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%. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=6110912

Lung volume reduction surgery
Cooper JD, Trulock EP, Triantafillou AN, et al. Bilateral pneumonectomy (volume reduction) for COPD. J Thorac Cardiovasc Surg 1995;109:106-19. This paper revived interest in LVRS for COPD and has generated lots of controversy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7815786

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11596586

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12759479

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=453709

Anthonisen NR. Prognosis in COPD: results from multicenter clinical trials. Am Rev Respir Dis 1989:140:S95-9. This analysis of previous trials found that COPD patients with hypoxemia had worse survival than non-hypoxemic COPD patients with equivalent FEV1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3510578

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14999112&query_hl=31

Casanova C, Cote C, Torres JP et al. Inspiratory- to- total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:591-7.  IC/TLC, a measure of static lung hyperinflation, predicted mortality independent of the BODE index.  The best IC/TLC value for death prediction on the receiver operating characteristic (ROC) type II curve was 25%, yielding a sensitivity and specificity of 0.71 and 0.69 respectively.  This was better than FEV1, but not as good as the BODE Index.  This study reflects a growing interest in using measures of hyperinflation to predict mortality and assess therapeutic response.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15591470