Correspondence
Outpatient Management of Severe COPD
N Engl J Med 2010; 363:493-495July 29, 2010
- Article
To the Editor:
Niewoehner (April 15 issue)1 reports that there are no serious safety problems associated with inhaled bronchodilators. We disagree.
First, the Towards a Revolution in COPD Health trial (TORCH; ClinicalTrials.gov number, NCT00268216) showed a significantly increased risk of serious pneumonia with the use of long-acting beta-agonist combinations (relative risk with inhaled corticosteroids plus long-acting beta-agonists vs. long-acting beta-agonists, 1.58; 95% confidence interval [CI], 1.24 to 2.01).2
Second, there was a significantly increased risk of intestinal obstruction (reported as adverse events) with the use of tiotropium (relative risk, 5.55; 95% CI, 1.24 to 24.8) in the Understanding Potential Long-Term Impacts on Function with Tiotropium study (UPLIFT; NCT00144339).3
Third, a Food and Drug Administration analysis of fatal adverse events in three long-term trials of tiotropium delivered by means of a Respimat inhaler (Tiotropium/Respimat One-Year Study, NCT00168844; Tiotropium/Respimat One-Year Study, NCT00168831; and Tiotropium/Respimat One-Year Study in COPD, NCT00387088) showed that there was “a numerical imbalance in mortality favoring placebo,” with tabulated data showing a total of 85 deaths among 3289 patients who received tiotropium (2.6%) as compared with 47 deaths among 2618 patients who received placebo (1.8%).3 The serious concerns about the cardiovascular risk associated with ipratropium4 and tiotropium delivered by Respimat should be clarified. We caution against undue reliance on data on cardiovascular safety from a single large trial (UPLIFT) in which electrocardiographic findings were not recorded,2 a large number of investigator-reported myocardial infarctions were not counted,5 and the ascertainment of cardiac deaths was incomplete (approximately 0.25% cardiac deaths per year). This lack of ascertainment of the rate of cardiac deaths in the UPLIFT study explains the differences between the UPLIFT study and the TORCH study (in which the rate of cardiac deaths was approximately 1% per year) despite the enrollment of populations with similar severity.
Sonal Singh, M.D., M.P.H.
Johns Hopkins University, Baltimore, MD
ssingh31@jhu.edu Yoon K. Loke, M.D.
University of East Anglia, Norwich, United KingdomCurt D. Furberg, M.D., Ph.D.
Wake Forest University, Winston-Salem, NCNo potential conflict of interest relevant to this letter was reported.
5 References1
Niewoehner DE . Outpatient management of severe COPD. N Engl J Med 2010;362:1407-1416
Full Text | Web of Science | Medline2
Singh S ,Amin AV ,Loke YK . Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med 2009;169:219-229
CrossRef | Web of Science | Medline3
FDA briefing document, November 19, 2009. Silver Spring, MD: Pulmonary-Allergy Drugs Advisory Committee and Office of Surveillance and Epidemiology, Food and Drug Administration, 2009. (Accessed July 8, 2010, at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM190463.pdf.)
4
Ogale SS ,Lee TA ,Au DH ,Boudreau DM ,Sullivan SD . Cardiovascular events associated with ipratropium bromide in COPD. Chest 2010;137:13-19
CrossRef | Web of Science | Medline5
Celli B ,Decramer M ,Kesten S , et al. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:948-955
CrossRef | Web of Science | Medline
To the Editor:
In his review, Niewoehner notes that chronic obstructive pulmonary disease (COPD) is the cause of a steadily increasing number of deaths in the United States. It is therefore essential to add to management a discussion of health care decision making and relief of suffering. Patients with advanced COPD have progressive functional decline, a poor quality of life, and increasing dependence on caregivers.1 Hospitalized patients with COPD are more likely than patients with cancer to receive life support, to die in the intensive care unit with unrelieved symptoms, and to never have a dialogue about health care preferences.2 The care of patients with advanced COPD should include an interdisciplinary approach that addresses the treatment of unrelieved symptoms, advance care planning, and psychosocial and spiritual support. Patients are entitled to an estimation of the prognosis to facilitate decision making. Specifically, a 6-month mortality of 30 to 40% can be anticipated among patients with two of the following: a baseline partial pressure of carbon dioxide in arterial blood of more than 45 mm Hg, a forced expiratory volume in 1 second of less than 0.75 liters, cor pulmonale, and more than one episode of respiratory failure in 1 year.3 A discussion about the potential benefits of hospice care is reasonable for such patients. Finally, opioids should be considered for the relief of dyspnea in patients with refractory disease.4
Michelle Z. Schultz, M.D.
St. Mary's Health Center, St. Louis, MO
michelle_schultz@ssmhc.com No potential conflict of interest relevant to this letter was reported.
4 References1
Au DH ,Udris EM ,Fihn SD ,McDonell MB ,Curtis JR . Differences in health care utilization at the end of life among patients with chronic obstructive pulmonary disease and patients with lung cancer. Arch Intern Med 2006;166:326-331
CrossRef | Web of Science | Medline2
Claessens MT ,Lynn J ,Zhong Z , et al. Dying with lung cancer or chronic obstructive pulmonary disease: insights from SUPPORT (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). J Am Geriatr Soc 2000;48:5 Suppl:S146-S153
Web of Science | Medline3
Connors AF Jr ,Dawson NV ,Thomas C , et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease: the SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med 1996;154:959-967[Erratum, Am J Respir Crit Care Med 1997;155:386.]
Web of Science | Medline4
Jennings AL ,Davies AN ,Higgins JPT ,Broadley K . Opioids for the palliation of breathlessness in terminal illness. Cochrane Database Syst Rev 2001;4:CD002066-CD002066
Medline
Author/Editor Response
Singh et al. question my statement that no serious safety problems with the use of long-acting bronchodilators were identified in the TORCH and UPLIFT trials.1,2 TORCH was a four-group trial that compared the use of placebo−placebo, salmeterol−placebo, fluticasone−placebo, and salmeterol−fluticasone in 6112 patients with COPD over 3 years, and the UPLIFT trial compared the use of tiotropium with placebo in 5993 similar patients over 4 years. Vital status at planned completion of the trial was ascertained for 95% of the patients randomly assigned in the UPLIFT trial and in all but a single patient in the TORCH trial. Panels that were unaware of the treatment assignments adjudicated all deaths in both trials. The size and duration of these two trials and, most importantly, the completeness of the resulting mortality data make them the most reliable sources of safety information for those particular drugs.
As compared with placebo controls, both salmeterol and tiotropium reduced the number of deaths from cardiovascular diseases and deaths from any cause, with differences that were statistically significant in some analyses.1,2 Combination therapy with salmeterol and fluticasone does increase the risk of pneumonia, but it is clearly evident from the TORCH trial and from other studies that this risk is due to fluticasone and not to salmeterol, as Singh et al. state. In the UPLIFT trial, intestinal obstructions reported as adverse events, but not serious adverse events, were significantly more common with the use of tiotropium (P<0.05). In the UPLIFT trial and all earlier trials of long-acting bronchodilators, the HandiHaler inhalation device was used for tiotropium administration. As Singh et al. note, three trials in which the newer Respimat inhalation device was used suggest excess mortality with the use of tiotropium as compared with placebo. There is an obvious need for additional safety studies of that particular device. The claims by Singh et al. that a large number of investigator-reported deaths from myocardial infarction were undercounted in the UPLIFT trial and that the ascertainment of cardiac deaths was incomplete have no factual basis. Investigators attributed 36 deaths to myocardial infarction, but the adjudication committee could confirm only 17 deaths by objective criteria.3 A separate analysis of deaths attributed to myocardial infarction by investigators showed a statistically nonsignificant reduction in deaths among the subjects who received tiotropium.
Schultz mentions that I did not address the care of patients with end-stage COPD. This is an important topic, and I was remiss in not discussing it.
Dennis E. Niewoehner, M.D.
Veterans Affairs Medical Center, Minneapolis, MN
niewo001@umn.edu Since publication of his article, the author reports no further potential conflict of interest.
3 References1
Calverley PMA ,Anderson JA ,Delli B , et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-789
Full Text | Web of Science | Medline2
Tashkin DP ,Celli B ,Senn S , et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543-1554
Full Text | Web of Science | Medline3
Celli B ,Decramer M ,Kesten S ,Liu D ,Mehra S ,Tashkin DP . Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:948-955
CrossRef | Web of Science | Medline
