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Drug Safety in COPD RevisitedDrug Safety in COPD: What Is the Number Needed to Analyze? FREE TO VIEW

Klaus F. Rabe, MD, PhD
Author and Funding Information

From the Christian Albrechts University Kiel, Department of Internal Medicine and Grosshansdorf Clinic.

Correspondence to: Klaus F. Rabe, MD, PhD, Grosshansdorf Clinic, Center of Pulmonary Diseases and Thoracic Surgery, Wöhrendamm 80, 22927 Grosshansdorf, Germany; e-mail: k.f.rabe@kh-grosshansdorf.de


Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(2):271-274. doi:10.1378/chest.12-1395
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Published online

The treatment of COPD worldwide relies on a rather limited selection of pharmacologic principles. Symptomatic benefit and improvement of lung function are afforded by β2-adrenoceptor agonists with largely comparable efficacy and varying durations of action, as well as short- and long-acting anticholinergic drugs, whereas the underlying inflammation in the airways (and systemically) is targeted by (mainly inhaled) corticosteroids and, more recently, orally applied selective phosphodiesterase-4 inhibitors.1,2

Since bronchodilator drugs primarily result in symptomatic benefit for patients with COPD, they are prescribed for all levels of disease severity and account for a huge number of prescriptions globally.3 Anticholinergic drugs have been used for the treatment of COPD for many years owing to their effects on lung function, exercise capacity, and exacerbations, starting with the introduction of ipratropium bromide, and later tiotropium, both of which are prescribed frequently and account for a sizeable portion of drug sales for COPD.4,5 β2-Adrenoceptor agonists, such as salbutamol (albuterol), with a short duration of action have a wide and global acceptance as rescue medication for dyspnea, whereas long-acting drugs, such as salmeterol and formoterol, are most frequently used in combination with inhaled corticosteroids for more severe disease and for patients with exacerbations of COPD. Real progress in the development of drugs for this highly prevalent disorder is unfortunately scarce, and so far the immediate “novel” developments appearing on the pharmaceutical market’s horizon are frequently modifications of existing pharmacologic principles or the combination of existing drugs mentioned here.

Drug treatment of frequent conditions such as COPD, a disease that most frequently occurs beyond the fifth decennium of life and is mainly caused by cigarette smoke, at least in Europe and in the United States, is frequently associated with vascular and cardiac disease.6-8 Bronchodilator drugs have the potential to be arrhythmogenic, based on their pharmacologic profile, and therefore specific and careful drug safety monitoring is mandated. Although safety aspects of β2-adrenoceptor agonists seem more frequently discussed in the context of long-term treatment of bronchial asthma, for anticholinergic drugs—short-acting ipratropium bromide in particular—an increased level of awareness in relation to cardiovascular events and strokes was noted in patients with COPD.

Over the last few years, a range of drug safety studies have appeared, including in CHEST, with somewhat conflicting results.9-17 The interpretation of such studies was often hampered by methodologic shortcomings and the quality and validity of reported data. Evidence for the (increased) occurrence of important and detrimental side effects could be collected prospectively if also mandated by regulatory bodies but all too often relies on the retrospective analysis of prescription databases, an approach that has inherent limitations and probably should, therefore, primarily serve to generate hypotheses to prospectively study certain aspects of drug safety of a given drug.

In the current issue of CHEST, two noteworthy articles by the same group of authors are published,18,19 contributing to the ongoing discussion on the safety of bronchodilator drugs in COPD. They also highlight some fundamental issues of study design and data analysis.

In the first report (see page 298),18 a database of 6,018 patients with COPD, aged 55 or more years, from the province of Saskatchewan, Canada, were retrospectively analyzed. The listings occurred between 1990 and 1999, at a time when the short-acting ipratropium was the anticholinergic of choice, and long-acting β-agonists were only available under specific prescription circumstances in that region. In this cohort, 469 arrhythmia cases (overall rate 1.37/100 patient-years) were reported, including 56 deaths. Compared with a nested control group, the risk of arrhythmia was increased with new use of ipratropium (rate ratio [RR], 2.4; 95% CI, 1.4-4.0) and long-acting β-agonists (RR, 4.5; 95% CI, 1.4-14.4), but it was not increased by short-acting β2-adrenoceptor agonists or, curiously, methylxanthines. The findings led the authors to conclude that the new use of ipratropium bromide in COPD is associated with an increased cardiac risk, as is the use of β-agonists, although they cautioned that the number of cases was low.

The second report (see page 305)19 is based again on the analysis of data from a database, this time 76,661 patients with COPD, aged 67 years or more, from the province of Quebec in Canada. Treatment occurred between 1990 and 1999 and was followed until 2003. Again, ipratropium was the anticholinergic of choice, but long-acting β2-adrenoceptor agonists were available to everyone and more frequently prescribed than in Saskatchewan. In this cohort, 5,307 cases of arrhythmia (overall rate, 1.03/100 patient-years) were reported, including 621 deaths. Compared with a nested control group, the risk of arrhythmia in this analysis was not significantly increased with new use of ipratropium (RR, 1.23; 95% CI, 0.95-1.57) but did demonstrate increased risk ratios for the new use of short-acting (RR, 1.27; 95% CI, 1.03-1.57) and long-acting β2-adrenoceptor agonists (RR, 1.47; 95% CI, 1.01-2.15).

As discussed by the authors, the most significant difference between the two studies presented side by side is the sample size and, in direct relation, the number of recorded events of arrhythmia, differing by a factor of nine. Although the initial study was conducted in what seems a sizeable group of individuals, it resulted in large CIs and thereby uncertainty in interpretation. The subsequent study provided more reliable data and significantly, changed the conclusion around the use of ipratropium to an apparently much smaller risk, while it highlighted the risks associated with the use of short- and long-acting β-adrenoceptor agonists.

The event rates in the two analyses were remarkably similar but low overall compared with later prospective trials, such as a 4-Year Trial of Tiotropium in COPD (UPLIFT) and Tiotropium vs Salmeterol for the Prevention of Exacerbations of COPD (POET),20,21 likely speaking to the general weakness of retrospective database analyses to capture relevant events. Another relevant specific bias lies in the fact that only cardiac events leading to hospitalization were recorded, favoring more severe episodes and, therefore, probably not at all adequately reflecting true incidence for atrial fibrillation.

Quite surprising and also concerning is the lack of very basic and important patient data in the databases under study, such as lung function, and clinical details, including smoking, adding to the known underreporting of events such as exacerbations, known to be associated with cardiac episodes. The lack of these data makes true assessment of COPD severity problematic, and prescription indication by severity and by perceived cardiac risk is difficult to control for. As with all retrospective studies of bronchodilator treatments, and highlighted earlier, ipratropium might be prescribed more readily to patients with known cardiac problems introducing bias in favor of other drug treatment.22 Another related issue, also acknowledged by the authors, is the introduction of protopathic bias in the analysis. This form of bias occurs when a treatment is given to a patient for a condition that is directly related to the outcome. For the present studies, this means specifically that a patient with presumed COPD might have become symptomatic because of cardiac comorbidities, such as heart failure, that can obviously contribute to dyspnea and is associated with arrhythmia.19 Although this type of bias probably cannot ever be ruled out completely, the lack of detailed patient data in the present database studies makes the contribution of this specific bias impossible to determine.

Dr Wilchesky and colleagues should be commended for conducting the type of research presented in their reports, despite and because of the lack of conclusive data on the safety of bronchodilator drugs in COPD from specifically designed prospective safety trials. A recent US Food and Drug Administration (FDA) panel that was convened to address the safety concerns of tiotropium, a long-acting anticholinergic drug, came to the conclusion—among others—that for the assessment of tiotropium safety prospective, FDA-controlled prospective trials are needed,23 but these data are not available as yet.

Somewhat surprisingly, the attention toward long-term safety of β-agonist use in COPD has been more limited, with hardly any prospective data, although the pharmacology of this class of drugs makes it likely that it can produce arrhythmogenic effects in the vulnerable population of patients with COPD.10,24,25 Interestingly, in a large prospective direct comparator trial between tiotropium and salmeterol for the treatment of COPD, no difference in cardiac adverse events was shown, with an RR of 1.12 (95% CI, 0.84-1.50) for tiotropium vs salmeterol at an event rate of 2.73 vs 2.44/100 patient-years, predictably being considerably higher than any of the database studies discussed here.21

Considering the (from a European perspective) very cautious approach of the FDA to mandate large safety assessments of long-acting β-agonists in asthma,26 it is interesting to speculate whether such an approach should and will be adopted for COPD in the future as well, also considering the data of the present reports. Furthermore, and with the upcoming interest for anticholinergics for the treatment of asthma, it is obvious that long-term safety in this condition also needs to be addressed in the future.

How to make sense of all of this, then, at the present time? Clinically, and based on the available evidence thus far, a scheme seems to be evolving: Frequent comorbidities of COPD (and in at-risk patients with asthma) need to be diagnosed and considered within the management and specifically in the selection of drugs. Among all comorbidities, chronic heart failure and arrhythmia are frequent comorbid conditions and should be assessed in all patients at risk.27 The reported absolute risks of bronchodilator medications for COPD are small and very likely outweighed by their benefits. However, for cardiac comorbidities and vascular risks the available evidence suggests that (1) anticholinergic drugs exhibit a favorable safety profile, and (2) the long-acting tiotropium appears preferable over short-acting ipratropium and over salmeterol, clearly if one considers efficacy and safety together.

Finally, I believe we have seen enough potentially flawed retrospective analyses of databases trying to assess drug safety of COPD drugs delivering conflicting and merely hypothesis-generating results. At the very least, epidemiologists should lead the field by establishing clear guidance as to the quality of datasets, statistical methods that are generally accepted and valid, including the number needed to analyze, the importance of which is demonstrated in the present back-to-back articles featured in this issue. In the end, the somewhat uncomfortable recommendations, including those of the FDA, are correct: If drug safety is at our hearts, we need to invest in this type of research and conduct the appropriate trials.

References

Miles MC, Donohue JF, Ohar JA. Optimum bronchodilator combinations in chronic obstructive pulmonary disease: what is the current evidence?. Drugs. 2012;72(3):301-308.
 
Hansel TT, Barnes PJ. New drugs for exacerbations of chronic obstructive pulmonary disease. Lancet. 2009;374(9691):744-755.
 
Dalal AA, Candrilli SD, Davis KL. Outcomes and costs associated with initial maintenance therapy with fluticasone propionate-salmeterol xinafoate 250 microg/50 microg combination versus tiotropium in commercially insured patients with COPD. Manag Care. 2011;20(8):46-50, 53-55.
 
Mauskopf JA, Baker CL, Monz BU, Juniper MD. Cost effectiveness of tiotropium for chronic obstructive pulmonary disease: a systematic review of the evidence. J Media Econ. 2010;13(3):403-417.
 
Zaniolo O, Iannazzo S, Pradelli L, Miravitlles M. Pharmacoeconomic evaluation of tiotropium bromide in the long-term treatment of chronic obstructive pulmonary disease (COPD) in Italy. Eur J Health Econ. 2012;13(1):71-80.
 
Johnston AK, Mannino DM, Hagan GW, Davis KJ, Kiri VA. Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middle-aged cohort. Thorax. 2008;63(7):599-605.
 
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.
 
Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation. 2003;107(11):1514-1519.
 
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.
 
Cazzola M, Matera MG, Donner CF. Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease. Drugs. 2005;65(12):1595-1610.
 
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.
 
Gershon AS, Wang L, To T, Luo J, Upshur RE. Survival with tiotropium compared to long-acting beta-2-agonists in chronic obstructive pulmonary disease. COPD. 2008;5(4):229-234.
 
Hilleman DE, Malesker MA, Morrow LE, Schuller D. A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2009;4:253-263.
 
Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety. Chest. 2006;130(6):1695-1703.
 
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.
 
Seider N, Abinader EG, Oliven A. Cardiac arrhythmias after inhaled bronchodilators in patients with COPD and ischemic heart disease. Chest. 1993;104(4):1070-1074.
 
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.
 
Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. Bronchodilator use and the risk of arrhythmia in COPD: part 1: Saskatchewan cohort study. Chest. 2012;142(2):298-304.
 
Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. Bronchodilator use and the risk of arrhythmia in COPD: part 2: reassessment in the larger Quebec cohort. Chest. 2012;142(2):305-311.
 
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.
 
Vogelmeier C, Hederer B, Glaab T, et al. POET-COPD Investigators Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-1103.
 
Rabe KF. Anticholinergic drugs for the treatment of COPD are safe… are they?. Chest. 2010;137(1):1-3.
 
Michele TM, Pinheiro S, Iyasu S. The safety of tiotropium—the FDA’s conclusions. N Engl J Med. 2010;363(12):1097-1099.
 
Salpeter SR. Bronchodilators in COPD: impact of beta-agonists and anticholinergics on severe exacerbations and mortality. Int J Chron Obstruct Pulmon Dis. 2007;2(1):11-18.
 
Salpeter SR. Cardiovascular safety of beta(2)-adrenoceptor agonist use in patients with obstructive airway disease: a systematic review. Drugs Aging. 2004;21(6):405-414.
 
FDA Drug Safety Communication FDA requires post-market safety trials for Long-Acting Beta-Agonists (LABAs) US Food and Drug Administration website.http://www.fda.gov/Drugs/DrugSafety/ucm251512.htm. Accessed June 2, 2012.
 
Nussbaumer-Ochsner Y, Rabe KF. Systemic manifestations of COPD. Chest. 2011;139(1):165-173.
 

Figures

Tables

References

Miles MC, Donohue JF, Ohar JA. Optimum bronchodilator combinations in chronic obstructive pulmonary disease: what is the current evidence?. Drugs. 2012;72(3):301-308.
 
Hansel TT, Barnes PJ. New drugs for exacerbations of chronic obstructive pulmonary disease. Lancet. 2009;374(9691):744-755.
 
Dalal AA, Candrilli SD, Davis KL. Outcomes and costs associated with initial maintenance therapy with fluticasone propionate-salmeterol xinafoate 250 microg/50 microg combination versus tiotropium in commercially insured patients with COPD. Manag Care. 2011;20(8):46-50, 53-55.
 
Mauskopf JA, Baker CL, Monz BU, Juniper MD. Cost effectiveness of tiotropium for chronic obstructive pulmonary disease: a systematic review of the evidence. J Media Econ. 2010;13(3):403-417.
 
Zaniolo O, Iannazzo S, Pradelli L, Miravitlles M. Pharmacoeconomic evaluation of tiotropium bromide in the long-term treatment of chronic obstructive pulmonary disease (COPD) in Italy. Eur J Health Econ. 2012;13(1):71-80.
 
Johnston AK, Mannino DM, Hagan GW, Davis KJ, Kiri VA. Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middle-aged cohort. Thorax. 2008;63(7):599-605.
 
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.
 
Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation. 2003;107(11):1514-1519.
 
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.
 
Cazzola M, Matera MG, Donner CF. Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease. Drugs. 2005;65(12):1595-1610.
 
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.
 
Gershon AS, Wang L, To T, Luo J, Upshur RE. Survival with tiotropium compared to long-acting beta-2-agonists in chronic obstructive pulmonary disease. COPD. 2008;5(4):229-234.
 
Hilleman DE, Malesker MA, Morrow LE, Schuller D. A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2009;4:253-263.
 
Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety. Chest. 2006;130(6):1695-1703.
 
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.
 
Seider N, Abinader EG, Oliven A. Cardiac arrhythmias after inhaled bronchodilators in patients with COPD and ischemic heart disease. Chest. 1993;104(4):1070-1074.
 
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.
 
Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. Bronchodilator use and the risk of arrhythmia in COPD: part 1: Saskatchewan cohort study. Chest. 2012;142(2):298-304.
 
Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. Bronchodilator use and the risk of arrhythmia in COPD: part 2: reassessment in the larger Quebec cohort. Chest. 2012;142(2):305-311.
 
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.
 
Vogelmeier C, Hederer B, Glaab T, et al. POET-COPD Investigators Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-1103.
 
Rabe KF. Anticholinergic drugs for the treatment of COPD are safe… are they?. Chest. 2010;137(1):1-3.
 
Michele TM, Pinheiro S, Iyasu S. The safety of tiotropium—the FDA’s conclusions. N Engl J Med. 2010;363(12):1097-1099.
 
Salpeter SR. Bronchodilators in COPD: impact of beta-agonists and anticholinergics on severe exacerbations and mortality. Int J Chron Obstruct Pulmon Dis. 2007;2(1):11-18.
 
Salpeter SR. Cardiovascular safety of beta(2)-adrenoceptor agonist use in patients with obstructive airway disease: a systematic review. Drugs Aging. 2004;21(6):405-414.
 
FDA Drug Safety Communication FDA requires post-market safety trials for Long-Acting Beta-Agonists (LABAs) US Food and Drug Administration website.http://www.fda.gov/Drugs/DrugSafety/ucm251512.htm. Accessed June 2, 2012.
 
Nussbaumer-Ochsner Y, Rabe KF. Systemic manifestations of COPD. Chest. 2011;139(1):165-173.
 
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