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Anticholinergic Drugs for the Treatment of COPD Are Safe â&#x20AC;Ś Are They? Klaus F. Rabe Chest 2010;137;1-3 DOI 10.1378/chest.09-2466

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Editorials CHEST | Volume 137 | Number 1 | January 2010

Anticholinergic Drugs for the Treatment of COPD Are Safe… Are They? is increasingly recognized as a complex sysCOPD temic disorder with a whole range of comorbidi-

ties, especially cardiovascular, contributing significantly to COPD morbidity and mortality.1 Among the most frequently prescribed inhaled medications for this disorder are anticholinergic agents, such as shortacting ipratropium bromide, available for 20 years, and the long-acting drug tiotropium bromide, introduced in 2002, which has been shown to improve airflow, hyperinflation, exercise tolerance, exacerbations of COPD, and health-related quality of life with oncedaily dosing2-8 in patients with COPD. Since these drugs are poorly absorbed by the gastrointestinal tract and the lungs, systemic adverse effects such as tachycardia are considered unlikely,9 and prescription habits might have been biased toward administering this class of drugs to patients with a higher perceived cardiovascular risk. However, for many years a link between anticholinergic drugs and an increased risk of mortality, especially from cardiovascular disease, has been reported10-14 and debated. Although there seems no reasonable explanation based on the pharmacology that short-acting anticholinergics would affect the cardiovascular system differently than long-acting drugs, a pattern seems to evolve favoring tiotropium over ipratropium also in terms of safety. Three recent publications again highlighted potential concerns in relation to short-acting anticholinergic ipratropium bromide and cardiovascular safety in patients with COPD. The metaanalysis by Singh et al14 seemed to indicate an increased risk for myocardial infarctions with a risk ratio (RR) of 1.53, (1.05-2.23) and cardiovascular death RR 1.80, (1.17-2.77) in patients randomized to inhaled anticholinergics. Similarly, two observational studies found an increased risk between anticholinergic use and cardiovascular events13 and cardiovascular-related mortality.12 The retrospective, nested case-control study by Lee et al12 focused on overall and cause-specific mortality examining the association between several respiratory medications and the risk of death in patients with newly www.chestjournal.org

diagnosed COPD. As a critical comment, this study likely contains relevant differences in baseline risk between the treatment groups, and there was no information available on smoking or lung function. The study by Singh et al14 selected randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke; the secondary outcome was all-cause mortality. The conclusion was that inhaled anticholinergics significantly increased the risk of the composite cardiovascular end point, myocardial infarction, and cardiovascular death, without a statistically significant increase in the risk of stroke. The study has been criticized for integrating placebo controlled trials with active controlled trials and because the analysis did not take into account differential discontinuation. Interestingly, also in this analysis, most of the evidence was provided by the Lung Health Study, which was conducted using ipratropium. Although the respiratory community has been amply confused in the recent past by post hoc and metaanalyses of treatment (side) effects in COPD, the persistence of these reports since the publication of the Lung Health Study is noteworthy. In contrast and as a reassurance, the recent prospective Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) study did not find an increase in cardiovascular adverse events in those randomized to tiotropium; the risk for fatal cardiovascular events was reduced (RR = 0.8), including patients for whom the specific cause of death was not specified.15 Also, a report of a pooled analysis of 19 clinical trials with tiotropium of up to 1 year in duration described data on a variety of selected safety end points.16 Contrary to the report by Singh et al,14 which suggested an increased relative risk for cardiovascular mortality of 1.8, the report from the 19 trials noted a decreased risk for fatal cardiovascular events in patients randomized to the anticholinergic with an RR of 0.57. In this issue of CHEST, this ongoing debate and discrepancy continues. Dr Ogale and colleagues17 present a cohort study of 82,717 US veterans with a new diagnosis of COPD established between 1999 and CHEST Ⲑ 137 Ⲑ 1 Ⲑ JANUARY, 2010

2002 (see page 13). The study essentially examines again the association between inhaled ipratropium bromide and cardiovascular events (CVEs), including the effects of inhaled corticosteroids, in patients with COPD. Subjects were followed until they had their first hospitalization for events such as acute coronary syndrome, heart failure, or cardiac dysrhythmia, or until death. Cumulative anticholinergic exposure was calculated as the number of 30-day equivalents within the past year. The study identified 6,234 cardiovascular events, and compared with subjects not exposed to anticholinergics within the past year, any exposure to anticholinergics within the past 6 months was associated with a significantly increased risk of a cardiac event. Surprisingly, in subjects who received anticholinergics more than 6 months prior, there did not appear to be elevated risk of CVE. The authors conclude that the study results are consistent with previous concerns raised about the cardiovascular safety of ipratropium bromide showing an increased risk of CVEs associated with the use of ipratropium within the past 6 months. The second article by Celli18 and colleagues in this issue of CHEST (see page 20) presents data from the clinical trial safety database for tiotropium. Trials with a duration of more than 4 weeks, and a randomized, double-blind, parallel-group, or placebocontrolled design were included, and importantly, adverse events were collected throughout each trial using standardized case report forms. Incidence rates were determined for all-cause mortality and selected CVEs, such as cardiovascular (CV) deaths, nonfatal myocardial infarction, nonfatal stroke, and the terms sudden death and (sudden) cardiac death. A total of 19,545 patients, (10,846 on tiotropium and 8,699 on placebo) from 30 trials were included with a cumulative exposure to tiotropium and placebo of 13,146 and 11,095 patient-years, respectively. For all-cause mortality, the incidence rate was 3.44 for tiotropium and 4.10 for placebo per 100 patient-years, and the other incidence rates all favored tiotropium over placebo. The analysis supports earlier conclusions that tiotropium is associated with a reduction in the risk of all-cause mortality, cardiovascular mortality, and cardiovascular events. Where do these two additional studies leave us? The Ogale study17 obviously has a number of limitations, including lacking data of patients not dying in the Veterans Affairs setting, the uncertainty of drug dispensing, the lack of some essential clinical data, and the concern about the unknown influence of prescription by severity. Nevertheless, in the chosen setting it adds to the persisting concern about short-acting anticholinergics and CV safety. Quite to the contrary, the tiotropium clinical trial program described by Celli et al18 represents a substantial database of 19,545

patients, and the results indicate that tiotropium reduces the risk for cardiovascular events, cardiovascular mortality, and all-cause mortality. It remains important for clinicians and patients to be aware of the potential benefits as well as the risks when making medication decisions for treatment of COPD. Judging from the available evidence so far, the long-acting tiotropium appears to be safe in CV terms, whereas retrospective large cohort analyses frequently conclude that the short-acting ipratropium has a small but consistent effect on CV safety that is unlikely to be explained by pharmacological differences of the drugs and therefore leaves broad room for speculation. In clinical and practical terms, the (more expensive) tiotropium appears to be the drug of choice. Given the vast investment required, it is unlikely that we will ever see the needed prospective trial that further clearly defines the CV risk of short-acting anticholinergics. The apparent differences in safety data between short- and long-acting anticholinergics are not easily explained. At the very least careful monitoring is mandatory. To this end, new efficacy and safety data from clinical trials with anticholinergic drugs, including new formulations used in the Respimat trials, are eagerly awaited. Klaus F. Rabe, MD, PhD Leiden, The Netherlands Affiliations: From the Department of Pulmonology, Leiden University Medical Center. FinancialⲐnonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Professor Rabe has consulted, participated in advisory boardmeetings, and received lecture fees from AstraZeneca, Boehringer, ChiesiPharmaceuticals, Pfizer, Novartis, Nycomed, Medical Specialties Distributors, and GlaxoSmithKline. Professor Rabe holds no stock or other equities in pharmaceutical companies. The Department of Pulmonology, and thereby Professor K. F. Rabe as head of the department, has received grants from Novartis, AstraZeneca, Boehringer Ingelheim, Nycomed, Roche and GlaxoSmithKline in the years 2005 until 2009. Correspondence to: Klaus F. Rabe, MD, PhD, Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands; e-mail: k.f.rabe@lumc.nl. © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.orgⲐ siteⲐmiscⲐreprints.xhtml). DOI: 10.1378Ⲑchest.09-2466

References 1. Fabbri LM, Luppi F, Beghé B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J. 2008;31(1):204-212. 2. Disse B, Speck GA, Rominger KL, Witek TJ, Jr, Hammer R. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci. 1999;64(6-7): 457-464. 3. Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002;19(2):217-224. 4. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months

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with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax. 2003;58(5):399-404. O’Donnell DE, Flüge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J. 2004;23(6):832-840. Maltais F, Hamilton A, Marciniuk D, et al. Improvements in symptom-limited exercise performance over 8 h with oncedaily tiotropium in patients with COPD. Chest. 2005;128(3): 1168-1178. 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(5):319-326. Tashkin DP, Celli B, Senn S, et al; UPLIFT Study investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554. Barnes PJ. The role of anticholinergics in chronic obstructive pulmonary disease. Am J Med. 2004;117(suppl 12A):24S-32S. Anthonisen NR, Connett JE, Enright PL, Manfreda J; Lung Health Study Research Group. Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med. 2002;166(3):333-339. Guite HF, Dundas R, Burney PG. Risk factors for death from asthma, chronic obstructive pulmonary disease, and cardiovascular disease after a hospital admission for asthma. Thorax. 1999;54(4):301-307. Lee TA, Pickard AS, Au DH, Bartle B, Weiss KB. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med. 2008;149(6):380-390. Macie C, Wooldrage K, Manfreda J, Anthonisen N. Cardiovascular morbidity and the use of inhaled bronchodilators. Int J Chron Obstruct Pulmon Dis. 2008;3(1):163-169. Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300(12):1439-1450. Tashkin D. Tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2009;360(2):187. Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety. Chest. 2006;130(6):16951703. Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. Cardiovascular events associated with ipratropium bromide in COPD. Chest. 2010;137(1):13-19. Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin DP. Cardiovascular safety of tiotropium in patients with COPD. Chest. 2010;137(1):20-30.

Primary vs Metastatic Pulmonary Adenocarcinoma Toward a Fuller Understanding of Truth

he article by Girard et al1 in this issue of CHEST (see page 46) focuses our attention upon an increasingly common clinical problem and offers us a practical and appealing new approach to solving it. Synchronous and metachronous pulmonary adenocarcinomas are discovered with growing frequency due to the development of more sensitive radiologic

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methods of detection, increased screening of smokers, closer postoperative surveillance, and other biologic factors that are not well understood. The prognosis and determination of the optimal treatment regimen depend upon whether the neoplasms represent independent, primary neoplasms or whether one represents a metastasis from the other. The importance of distinguishing multiple primary lung cancers from a single cancer with metastasis has prompted the development of criteria to differentiate between these scenarios. Criteria for accepting multiple carcinomas as primary in the lung were published in 1975 by Martini and Melamed.2 These criteria included histologic difference or histologic similarity with origin from carcinoma in situ, lack of carcinoma in lymphatics common to both tumors, and absence of extrapulmonary metastases; location in separate, physically distinct sites was added to this list for synchronous tumors, and a 2-year or greater time interval between cancers was included for metachronous tumors.2 In 2007, this topic was addressed and recommendations were published as part of the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines.3 The criteria included similar types of data, but also allowed for consideration of data about molecular genetic characteristics.3 Applying the criteria of Martini and Melamed, Girard and colleagues found six patients to have multiple primary adenocarcinomas and one to have metastatic adenocarcinoma; the ACCP criteria yielded three examples of multiple primary adenocarcinoma, three metastatic adenocarcinomas, and one indeterminate case.1 When the authors analyzed these cases for common epidermal growth factor receptor kinase domain mutations and Kirsten-rat sarcoma 2 viral oncogene homolog mutations, the adenocarcinomas comprising each set of paired neoplasms harbored different mutations and could therefore be classified as multiple primary adenocarcinomas, assuming that different mutations arise in independent clones.1 Comprehensive histologic subtyping was also performed on all of these tumors, which included 13 examples of adenocarcinoma of mixed subtypes and one pleomorphic carcinoma, and supported an independent origin for each tumor in each pair.1 Although the number of cases evaluated by Girard and colleagues1 was small, their results illustrate the need to incorporate molecular information into our categorization scheme for multiple lung neoplasms. Another recently published study using loss of heterozygosity studies, TP53 mutation screening analyses, and evaluations of X-chromosome inactivation patterns to assess patients with multiple lung tumors further highlights the utility of molecular methods for offering insight into this question.4 Larger-scale integration of molecular data into clinical decision making was CHEST Ⲑ 137 Ⲑ 1 Ⲑ JANUARY, 2010

Anticholinergic Drugs for the Treatment of COPD Are Safeâ&#x20AC;Ś Are They? Klaus F. Rabe Chest 2010;137; 1-3 DOI 10.1378/chest.09-2466 This information is current as of February 2, 2010 Updated Information & Services

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References

This article cites 18 articles, 13 of which can be accessed free at: http://chestjournal.chestpubs.org/content/137/1/1.fu ll.html#ref-list-1

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