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Recent safety issues with inhaled treatments for COPD
Volume 19 Number 4
April 2009

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Introduction What are the benefits of long-acting bronchodilators and ICSs for patients with COPD? What are the safety issues with LABAs in COPD? What are the safety issues with anticholinergics in COPD? What are the safety issues with ICSs in COPD? What needs to be considered when treatment choices are made?

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Introduction

Guidance on the management of chronic obstructive pulmonary disease (COPD) is given in the NICE clinical guideline on COPD,¹ which was published in 2004. A partial update to this guidance is due to be issued in June 2010. The NICE clinical guideline recommends a number of inhaled treatments for COPD including: short-acting beta2 agonists, e.g. salbutamol; long-acting beta2 agonists (LABAs), e.g. salmeterol or formoterol; short-acting anticholinergics, e.g. ipratropium; long-acting anticholinergics e.g. tiotropium; and inhaled corticosteroids (ICSs).

Long-acting bronchodilators (either a LABA or tiotropium) are recommended for patients who remain symptomatic on short-acting drugs, or in those who have two or more exacerbations requiring treatment with antibiotics or oral corticosteroids per year.¹ Adding in an ICS (usually in combination with a LABA) is recommended for patients with an FEV1 less than or equal to 50% predicted who are having two or more exacerbations per year, or if the patient remains symptomatic despite a long-acting bronchodilator.¹

Recently, a number of safety concerns have emerged with anticholinergics, LABAs and ICSs that may impact on treatment choices for some patients. This Bulletin reviews this new information and sets it in the context of the potential benefits these treatments have in patients with COPD. A previous MeReC Bulletin, Volume 19 No. 2, September 2008 (Current issues in the drug treatment of asthma ) looked at safety concerns with LABAs and ICSs in asthma. More general information on the management of COPD can be found on the relevant floor of NPCi.

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What are the benefits of long-acting bronchodilators and ICSs for patients with COPD?

Inhaled treatments are given to patients with COPD to improve their symptoms, i.e. breathlessness and exercise limitation, to reduce the frequency of exacerbations and to slow the decline in health status.¹ LABAs, tiotropium, and combination LABA/ICSs all reduce total exacerbations in patients with COPD, with absolute benefits likely to be greater in those patients who exacerbate frequently. The effects of these drugs compared with placebo and each other on reducing the risk of severe exacerbations requiring hospitalisation and death in patients with COPD is less well established.

So, what is the detail here? Well, compared with placebo, LABAs alone reduce exacerbations in patients with COPD, including those severe enough to require hospitalisation, but do not statistically significantly reduce deaths due to respiratory or all causes.^2,3 Tiotropium, again compared with placebo, also reduces total exacerbations and hospitalisations related to COPD,^4,5 although no statistically significant reduction in exacerbations requiring hospitalisation was seen with tiotropium in the large, four-year randomised controlled trial (RCT), UPLIFT.⁶ As with LABAs, tiotropium has not demonstrated a statistically significantly reduction in death due to all causes in patients with COPD.^4,6

Some pooled analyses have suggested that tiotropium is superior to LABAs in reducing severe exacerbations² and COPD-related hospitalisations.⁴ However, this is not the case in all analyses,⁵ and without a large, long-term prospective RCT directly comparing the efficacy of tiotropium and LABAs on clinically important outcomes for patients, the situation will remain unclear.

Treatment with ICSs alone, i.e. not combined with a LABA (an unlicensed use), has been shown to reduce total exacerbations in patients with COPD.^3,7 However, exacerbations requiring hospitalisation were not statistically significantly reduced with fluticasone alone in the large, three-year RCT, TORCH,³ and ICSs alone do not significantly affect mortality in patients with COPD.^3,7-9

Many patients taking ICSs for COPD use a combination LABA/ICS inhaler. In TORCH, salmeterol/fluticasone compared with salmeterol alone reduced exacerbations overall, but not those requiring hospitalisation.³ Death from COPD or all causes was also not statistically significantly reduced with the addition of fluticasone to salmeterol.³ In a Cochrane review of LABA/ICS combinations, combination treatment versus LABAs alone reduced total exacerbations, but there was no reduction in all-cause mortality.¹⁰ Compared with placebo, LABA/ICS combinations reduced severe exacerbations requiring hospitalisation in TORCH,³ but did not statistically significantly reduce death from all causes in the adjusted analysis.³ Using the unadjusted mortality analysis from TORCH, the Cochrane review¹¹ found all-cause mortality was statistically significantly reduced with LABA/ICS combinations compared with placebo.

One study, INSPIRE,¹² has compared LABA/ICS treatment with tiotropium in patients with severe COPD. INSPIRE found no difference between salmeterol/fluticasone and tiotropium in total exacerbation rates over a two-year period.¹² An unexpected finding was a lower rate of all-cause mortality with salmeterol/fluticasone, but the study was not designed or powered for this outcome and further trials designed to study mortality are needed to confirm this.¹²

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What are the safety issues with LABAs in COPD?

In patients with asthma, safety concerns about the use of LABAs arose when the Salmeterol Multicenter Asthma Research Trial (SMART) found that there were more respiratory-related deaths, asthma-related deaths, and combined asthma-related deaths or life-threatening experiences in the salmeterol group than in the placebo group.¹³ Whether similar safety concerns are true in patients with COPD is unclear. There are some data around this issue, as outlined below. However, COPD is a different disease to asthma, and findings from the ongoing MHRA review of LABAs in COPD are awaited to guide practice.¹⁴

In patients with asthma, safety concerns about the use of LABAs arose when the Salmeterol Multicenter Asthma Research Trial (SMART) found that there were more respiratory-related deaths, asthma-related deaths, and combined asthma-related deaths or life-threatening experiences in the salmeterol group than in the placebo group.¹³ Whether similar safety concerns are true in patients with COPD is unclear. There are some data around this issue, as outlined below. However, COPD is a different disease to asthma, and findings from the ongoing MHRA review of LABAs in COPD are awaited to guide practice.¹⁴

A meta-analysis by Salpeter et al in 2006¹⁵ reported concerns over regular beta₂ agonist use in patients with COPD. This found that short- and long-acting beta₂ agonists (pooled) significantly increased the risk of death from respiratory causes compared with placebo (relative risk [RR] 2.47, 95% confidence interval [CI] 1.12 to 5.45). However, this meta-analysis had several methodological flaws. It pooled results from both short- and long-acting bronchodilators, possibly double-counted some data and had only small numbers of events in some analyses, particularly those relating to death.

Reassurance about the safety of LABAs in patients with COPD comes from TORCH,³ published in 2007, and a subsequent meta-analysis by Rodrigo et al,² which included this large RCT. This meta-analysis found there was no significant increase in death from respiratory (RR 1.09, 95%CI 0.45 to 2.64) or all causes (RR 0.90, 95%CI 0.76 to 1.06) with LABAs compared with placebo, but neither were deaths significantly reduced.²

TORCH compared the effects of a LABA/ICS combination (salmeterol/fluticasone) with placebo, salmeterol alone or fluticasone alone in 6,112 patients with COPD.³ The primary outcome was death from any cause for the comparison between the combination regimen and placebo. After three years, the proportion of deaths in the combination treatment group was not statistically significantly different from that in the placebo group (12.6% vs. 15.2%, respectively; hazard ratio [HR] 0.83, 95%CI 0.68 to 1.00, P=0.052 [adjusted for interim analysis]). Likewise, there was no statistically significant difference between salmeterol alone and placebo in all-cause mortality (13.5% vs. 15.2%, respectively; HR 0.88, 95%CI 0.73 to 1.06, P=0.18 [unadjusted]).³ More detail on TORCH can be found in MeReC Extra No. 28, May 2007.¹⁶

An American observational study¹⁷ also provides some reassurance of the safety of LABAs. The odds ratio (OR) for all-cause mortality in patients taking LABAs compared with those not taking LABAs was 0.92, 95%CI 0.88 to 0.96. Respiratory and CV mortality or a combination of both were also not statistically significantly different. However, this study was unable to fully control for some risk factors, such as smoking status, making the conclusions less reliable.¹⁷

In summary, the safety concerns about the effect of LABAs on respiratory death rates in patients with COPD come from a retrospective pooled analysis of data. Such analyses have inherent limitations and only flag up potential safety issues, not confirm them. More recent data from a further meta-analysis, an observational study and a large RCT are reassuring about the safety of these drugs. However, in view of the concerns raised about the safety of LABAs in asthma, the MHRA continues to monitor the safety of these drugs in both asthma and COPD.¹

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What are the safety issues with anticholinergics in COPD?

In 2008, a meta-analysis by Singh et al¹⁸ and an observational study¹⁷ raised concerns that short- and long-acting anticholinergics may be associated with increased cardiovascular (CV) events and CV mortality in patients with COPD.

The meta-analysis by Singh et al found that inhaled anticholinergics significantly increased the composite outcome of CV death, myocardial infarction (MI) and stroke compared with control therapy (1.8% vs. 1.2%; RR 1.58, 95%CI 1.21 to 2.06, P<0.001).¹⁸ Anticholinergics increased the risk of death from CV causes and MI, but there was no statistically significant increase in the risk of stroke or all-cause mortality.¹⁸ When ipratropium and tiotropium were analysed separately, a significant increase in the composite outcome was seen with ipratropium in pooled analyses of short-term trials (<6 months duration), long-term trials (>6 months duration), and all trials combined. For tiotropium, an increase in the composite outcome was seen in pooled analyses of the four long-term trials, but not in the short-term trials or all tiotropium trials combined.

Like the Salpeter meta-analysis¹⁵ discussed above, the meta-analysis by Singh et al¹⁸ can be criticised on methodological grounds, particularly because it pooled results for short- and long-acting anticholinergics. More detail on this meta-analysis, including its limitations, can be found in MeReC Rapid Review blog No. 205.¹⁹

In the American observational study,¹⁷ patients taking ipratropium had a significantly increased risk of CV and all-cause mortality compared with patients not taking this drug (OR for all-cause mortality 1.11, 95%CI 1.08 to 1.15, OR for CV death 1.34, 95%CI 1.22 to 1.47).¹⁷ This study did not consider the use of tiotropium.

Retrospective pooled analyses and observational data both provide early information about potential safety issues. However, they have inherent limitations and uncertainty that require further investigation, ideally in prospective RCTs. Since the two studies outlined above were published, results from a large RCT of tiotropium, UPLIFT, have become available.⁶

UPLIFT randomised 5,993 people with COPD to tiotropium or placebo for four years. No significant benefit in the primary outcome of decline in FEV1 was detected.⁶ (The only intervention that reduces the rate of FEV1 decline in patients with COPD is smoking cessation.²⁰) There were benefits in secondary outcomes, including exacerbations (but not those leading to hospitalisation).⁶ All-cause mortality and rates of MI and stroke were reported and, although the trial was not originally designed to look at these latter cause-specific outcomes, no increase in any of these events was observed for tiotropium compared with placebo (HR for all-cause mortality 0.89, 95%CI 0.79 to 1.02, P=0.09; RR for MI 0.73, 95%CI 0.53 to 1.00; RR for stroke 0.95, 95%CI 0.70 to 1.29).⁶ When adverse events rather than efficacy outcomes were analysed from this study, there was a statistically significant reduction in fatal events in the tiotropium group compared with the placebo group (12.8% vs. 13.7%; HR 0.84, 95%CI 0.73 to 0.97).

The results from UPLIFT do provide reassurance on the CV safety of tiotropium, but the trial was not specifically designed to look at any CV endpoints. There may have been differences in how these outcomes were reported, or too few events to show any differences between the two groups if they really existed. Also of note is the fact that patients with a recent history of MI, arrhythmia or heart failure were excluded from the study.²¹ Therefore, it is not known whether these patients may be at an increased risk of any drug-related CV events in a real-world setting. Further details of the UPLIFT study are available in MeReC Rapid Review blog No. 223 .²²

The MHRA, in the November 2008 issue of Drug Safety Update, concluded that the conflicting findings from the recently published studies make it difficult to draw firm conclusions on the risk of all-cause mortality, CV death, or stroke associated with inhaled anticholinergics, and further analyses are needed to shed light on any possible increased risk.²³

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What are the safety issues with ICSs in COPD?

The potential risks of ICS treatment range from unpleasant local side effects, such as oral candidiasis and dysphonia, to less common systemic effects, such as adrenal suppression and osteoporosis. Recently, ICS treatment in patients with COPD has also been associated with an increased risk of pneumonia.

In TORCH, which compared the salmeterol/fluticasone combination with each drug individually and placebo, the percentages of patients with pneumonia over the three-year trial period were: 19.6% with combination treatment, 18.3% with fluticasone, 13.3% with salmeterol and 12.3% with placebo (P<0.001 for combination vs. placebo, combination vs. salmeterol and fluticasone vs. placebo).³ Similarly, the INSPIRE study, a head-to-head comparison of salmeterol/fluticasone with tiotropium found the risk of pneumonia was almost doubled in the combination group (8% vs. 4%; HR for time to pneumonia 1.94, 95%CI 1.19 to 3.17, P=0.008).¹² It should be noted that in both these studies, the diagnosis of pneumonia was based on clinical judgement, with radiographic confirmation not necessarily obtained.

Subsequent meta-analyses have also highlighted an increased risk of pneumonia in COPD patients treated with ICSs compared with non-ICS therapy. A meta-analysis by Drummond et al⁸ found the incidence of pneumonia was 14.4% in the ICS group compared with 10.4% in the control group (RR 1.34, 95%CI 1.03 to 1.75, P=0.03). A meta-analysis by Singh et al,⁹ found a significantly increased risk of any pneumonia (7.4% vs. 4.7%; RR 1.60, 95%CI 1.33 to 1.92, P<0.001) and serious pneumonia (5.2% vs. 3.1%; RR 1.71, 95%CI 1.46 to 1.99, P<0.001) with the use of ICSs compared with controls, but no increase in pneumonia-related mortality. In the Cochrane review of LABA/ICS combinations, combination therapy increased pneumonia compared with LABAs alone (OR 1.58, 95%CI 1.32 to 1.88)¹⁰ and placebo (OR 1.83, 95%CI 1.51 to 2.21).¹¹

In an attempt to explore more fully the association with ICS use and pneumonia, the meta-analysis by Drummond et al⁸ explored several subgroup analyses, which should only be viewed as hypothesis generating. They found that there was a significantly higher risk of pneumonia in the following subgroups: highest ICS dose (>1000 micrograms beclometasone equivalent); shorter (<2 years) duration of ICS use; higher baseline COPD severity (mean FEV1 <40% predicted) and combination therapy.⁸

In their clinical guideline on COPD, NICE state that, "clinicians should be aware of the potential risk of developing osteoporosis and other side effects in patients treated with high-dose ICSs (especially in the presence of other risk factors), and should discuss the risk with patients".¹ The data outlined above suggest that the potential increased risk of pneumonia from ICS use should also feature in these discussions.

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What needs to be considered when treatment choices are made?

When reviewing this safety information in the context of the NICE clinical guideline,¹ questions emerge over which long-acting bronchodilator is preferable when these are indicated, and what issues need to be thought about when considering the addition of an ICS to therapy.

When decisions are made around which bronchodilator to use, NICE advises that choice in individual patients should take account of their response to a trial of the drug, the drug's side effects, patient preference and cost.¹ The recently published safety data, as well as the potential benefits from treatment, should also feature in these decisions. Considering each drug in terms of its efficacy, safety, patient factors and cost can help prescribers and patients make an informed choice about which drug to use, see Table.

The safety concerns discussed above about the effect of LABAs on respiratory death rates and the CV safety of tiotropium come from retrospective pooled analyses of data. These analyses have inherent limitations and only flag up potential safety issues, not confirm them. More recent, large RCTs of LABAs and tiotropium have been reassuring about their safety. However, continued monitoring of these drugs is required and, for the present, patients and prescribers should balance these new data in their discussions.

Before adding an ICS to treatment regimens for patients with COPD, prescribers should consider, and discuss with patients, the potential increased risk of pneumonia, as well as osteoporosis and other side effects.

Treatment for COPD should be offered as therapeutic trials which should be discontinued if there is no benefit. If treatment is given for symptom control alone, NICE currently recommend that combination treatment should be discontinued after four weeks if there is no benefit.¹ However, as combination treatment is often given to reduce the frequency of exacerbations and improve quality of life, longer term treatment will be required.

The safety and efficacy issues summarised in the Table may provide a starting point for discussions with patients about which treatment to trial first, but the individual choice will probably depend more on whether they can use the inhaler device, tolerate the drug and how effective the medication is for their symptoms. COPD is a heterogeneous disease that affects different patients in different ways, and the management of an individual patient's disease should be guided by the symptoms and disability that they experience. The management of severe COPD has a large palliative element and focuses on symptom control and optimising quality of life.²⁴

NICE recommendations for the use of long-acting bronchodilators and ICSs are supported by the available evidence.¹ Long-acting bronchodilators (either a LABA or tiotropium) are recommended for patients who remain symptomatic on short-acting drugs, or in those who have two or more exacerbations per year.¹ Adding in an ICS (usually in combination with a LABA) is only recommended for patients with an FEV1 less than or equal to 50% predicted who are having two or more exacerbations requiring treatment with antibiotics or oral corticosteroids per year, or if the patient remains symptomatic despite a long-acting bronchodilator.

Reviewing whether the prescribing of these treatments fits with this guidance in individual patients provides an opportunity to minimise any potential risks of adding in treatments where no convincing evidence of benefit exists. It also provides an opportunity to possibly improve symptom control or reduce exacerbations if indicated treatments have not yet been trialled.

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References

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References

1. NICE. Chronic Obstructive Pulmonary Disease: Management of chronic obstructive pulmonary disease in adults in primary and secondary care. Clinical Guideline 12. 2004
2. Rodrigo GJ, Nannini LJ, Rodriguez-Roisin R. Safety of long-acting ß2-agonists in stable COPD: A systematic review. Chest 2008;133:1079-87

3. Calverley PMA, 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

4. Rodrigo GJ, Nannini LJ. Tiotropium for the treatment of stable chronic obstructive pulmonary disease: A systematic review with meta-analysis. Pulm Pharmacol Ther 2007;20:495-502

5. Barr RG, Bourbeau J, Camargo CA. Tiotropium for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD002876. DOI: 10.1002/14651858.CD002876.pub2

6. Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543-54

7. Yang IA, Fong K, Sim EH, et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD002991. DOI: 10.1002/14651858.CD002991.pub2

8. Drummond MB, Dasenbrook EC, Pitz MW, et al. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease. A systematic review and meta-analysis. JAMA 2008;300:2407-16

9. Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease. Arch Intern Med 2009;169:219-29

10. Nannini LJ, Cates CJ, Lasserson TJ, et al. Combined corticosteroid and long-acting beta-agonist in one inhaler versus long-acting beta-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829

11. Nannini LJ, Cates CJ, Lasserson TJ, et al. Combined corticosteroid and long-acting beta-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003794. DOI: 10.1002/14651858.CD003794.pub3

12. Wedzicha JA, Calverley PMA, 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

13. MHRA. Asthma: Long-acting β2 agonists. Available from www.mhra.gov.uk

14. MHRA review of formoterol and salmeterol in asthma and chronic obstructive pulmonary disease. 29th August 2008. Available from www.mhra.gov.uk

15. Salpeter SR, Buckley NS, Salpeter EE. Meta-analysis: Anticholinergics, but not ?-agonists, reduce severe exacerbations and respiratory mortality in COPD. J Gen Intern Med 2006;21:1011-9

16. NPC. Does TORCH shed light on COPD management? MeReC Extra Issue No. 28 May 2007

17. Lee TA, Pickard AS, Au DH, et al. Risk for Death Associated with Medications for Recently Diagnosed Chronic Obstructive Pulmonary Disease. Ann Intern Med 2008;149:380-90

18. Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease. JAMA 2008;300:1439-50

19. NPC. Anticholinergics in COPD - new data on cardiovascular safety. MeReC Rapid Review Blog no. 205

20. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994;272:1497-505

21. Boehringer Ingelheim and Pfizer. Information on the UPLIFT study. Available from www.upliftcopd.com

22. NPC. UPLIFTing data on tiotropium? - keep your feet on the ground. MeReC Rapid Review Blog No. 223

23. MHRA/CSM. Inhaled anticholinergics: recent published data for risk of death or stroke. Drug Safety Update November 2008

24. The National Collaborating Centre for Chronic Conditions. Chronic obstructive pulmonary disease. National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax 2004;59(Suppl I):1-232

25. Barber N. What constitutes good prescribing? BMJ 1995;310:923-5

26. Electronic Drug Tariff, NHS Business Services Authority, March 2009. Available from www.ppa.org.uk/ppa/edt_intro.htm

27. British National Formulary, Issue 57, March 2009, BMJ Group and RPS Publishing 2009

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