NPC Archive Item: More data on tiotropium compared with salmeterol in reducing exacerbations in COPD

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Date amended 20 May 2011
Date originally posted 28 April 2011

The POET-COPD randomised controlled trial found that tiotropium reduced the risk of moderate or severe exacerbations, compared with salmeterol, in people with moderate to very severe COPD (FEV1 70% predicted or less) with a history of exacerbations. Because of the use of inhaled corticosteroids in this study, application to people with severe or very severe disease in the context of NICE guidance is more complicated.

Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.

Health professionals looking after people with COPD should follow NICE guidance. This advises that people who experience exacerbations or persistent breathlessness despite use of a short-acting bronchodilator should be offered either a long-acting muscarinic antagonist (LAMA) or a long-acting beta agonist (LABA). If the option of a LABA is chosen in people with severe to very severe COPD (FEV1 <50% predicted) it should be offered in combination with an inhaled corticosteroid (ICS). The only LAMA currently licensed is tiotropium.

However, NICE does not give preference to either of these options. Given that a choice of treatment for an individual patient has to be made, health professionals and patients may wish to consider the outcomes of this study along with other factors such as the suitability to the individual of different inhaler devices, individual tolerability to treatment and, where relevant, possible adverse effects of inhaled corticosteroids.

What is the background to this?
The NICE guideline development group agreed that both classes of drug, LAMA and LABA, are clinically effective in COPD and there was no strong evidence (at the time the guidance was written) to favour one over the other. This study aimed to compare the effectiveness of tiotropium with the LABA salmeterol in preventing exacerbations in people who had had at least one exacerbation requiring treatment with antibiotics and/or corticosteroids (moderate exacerbations) or hospitalisation (severe exacerbations) in the previous year.

What does this study claim?
The primary outcome was the time to the first exacerbation (moderate or severe, as above). This was longer in the tiotropium group than in the salmeterol group (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.77 to 0.90, P<0.001). A similar effect was seen when this was considered according to the type of exacerbation: the HR for moderate exacerbations was 0.86 (95%CI 0.79 to 0.93, P<0.001) and for severe exacerbations it was 0.72 (95%CI 0.61 to 0.85).

Tiotropium significantly reduced the annual rate of exacerbations (0.64 vs. 0.72; rate ratio 0.89, 95%CI, 0.83 to 0.96, P=0.002), compared with salmeterol. When the different types of exacerbation were considered separately, tiotropium was found to have reduced the rates of both moderate exacerbations (0.54 vs. 0.59, rate ratio 0.93, 95%CI 0.86 to 1.00, P=0.048) and severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95%CI, 0.66 to 0.82; P<0.001). The number needed to treat (NNT) to prevent at least one exacerbation of either type over one year was 24. The NNT to prevent at least one moderate exacerbation was 36 over one year, and the NNT to prevent at least one severe exacerbation was 48 over one year.

The authors present a number of pre-specified post hoc analyses, two of which are pertinent here, one stratified by inhaled corticosteroid use (irrespective of disease severity) and another by severity of disease (irrespective of inhaled corticosteroid use). In patients who used concomitant inhaled corticosteroids during the study, the HR for time to first exacerbation was 0.91 (95%CI, 0.82 to 1.02), and it was 0.81 (95%CI, 0.72 to 0.91) in those who did not. The 95%CIs for the HRs in these two subgroups overlap and the authors conclude that the effect of tiotropium was independent of the concomitant use of inhaled corticosteroids. An alternative interpretation is that, since the 95%CI for the HR in the users of inhaled corticosteroids includes 1.00, this was not statistically significant and so the study cannot exclude the possibility that there is no true difference between tiotropium plus ICS and salmeterol plus ICS.

The HR was statistically significant in favour of tiotropium compared to salmeterol in all classes of disease severity. In patients with moderate disease (FEV1 50% to 79% predicted) the HR was similar to the HR in those with severe disease (FEV1 30% to 49% predicted): HR 0.88, 95%CI 0.79 to 0.99 and 0.86, 95%CI 0.77 to 0.97 respectively. The HR in those with very severe disease (FEV1<30%) was smaller, i.e. a greater effect (HR 0.64, 95%CI 0.50 to 0.81) but the 95%CIs for all these subgroups overlap, so the study cannot exclude the possibility that the observed between-group differences arose by chance, at conventional levels of statistical significance.

So what?
Following NICE guidance, people with COPD who experience exacerbations or persistent breathlessness despite use of a short-acting bronchodilator have a choice — should they first try a LAMA (currently tiotropium) or a LABA (LABA+ICS if their FEV1 is <50% predicted)? In some cases, patients will have a clear preference based on factors such as their ability to use one type of inhaler device over another. The acquisition cost of tiotropium is currently greater than LABA alone but less than combination LABA+ICS. For some patients, consideration must be given to the risks associated with inhaled corticosteroids, especially at the doses licensed in COPD, including diabetes, pneumonia, and psychological and behavioural effects, in addition to the more widely known systemic effects of inhaled corticosteroids. This study adds to the information which professionals and patients will want to consider.

Interpretation of the study in the context of NICE guidance is complicated by the fact that patients were allowed to continue treatment with inhaled corticosteroids during the study. Use of inhaled corticosteroids at baseline was evenly distributed between the groups, but does not appear to have been taken into account during randomisation, and it also appears that some patients may have discontinued or commenced inhaled corticosteroids during the study. Tiotropium plus ICS is not a regimen recommended within NICE guidance (because no evidence was found which met the guidance inclusion criteria). The ideal subgroup analyses to allow interpretation in the context of NICE guidance would have included tiotropium versus salmeterol (with no inhaled corticosteroid use in either group) in people with FEV1 50% predicted or greater, and tiotropium versus salmeterol plus ICS in people with FEV1 less than 50% predicted. These analyses were not available.

Exacerbation rates are important to patients because they are distressing and impair patients’ (and carers’) quality of life, and they are important to commissioners because of the costs of managing them, especially the costs of hospital admission. However, this study provides no information on how tiotropium and salmeterol compare with regard to outcomes other than exacerbations, such as breathlessness, or how they compare in patients with mild COPD (FEV1 80% predicted or greater). In addition, the comparator LABA used here was salmeterol: the study provides no information about comparisons with other LABAs.

Note: this is a revised version of this Rapid Review. The previously published version gave NNTs which were incorrectly calculated from event rates rather than from the proportions of patients who experienced one or more exacerbations. We are grateful for feedback which alerted us to this.

Study details
Vogelmeier C, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093–103

Design Double blind, double dummy, randomised controlled trial

Patients 7376 patients ≥40 years with moderate to very severe COPD (mean post-bronchodilator FEV1 49.3% predicted). Patients had a history of at least one exacerbation in the previous year.

Intervention and comparison Tiotropium 18microg per day via Handihaler versus salmeterol 50 microg twice daily via metered dose inhaler (MDI) for one year. Patients were allowed to continue their usual medications for COPD, except for antimuscarinic drugs and LABAs, during the double-blind treatment phase. At baseline, 53% of both groups were using ICS, 2% were taking oral corticosteroids, 30% were using tiotropium, 29% were using short-acting antimuscarinic drugs, 51% were using LABAs, 53% were using short-acting beta agonists, and about 22% were using methylxanthines.

Outcomes and results Outcomes related to exacerbations, defined as an increase in or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnea, or chest tightness), with at least one symptom lasting three days or more and leading the patient’s attending physician to initiate treatment with oral corticosteroids, antibiotics, or both (criterion for moderate exacerbation) or to hospitalise the patient (criterion for severe exacerbation). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (time for at least 25% of patients in each group to have a first exacerbation 187 days vs. 145 days, HR, 0.83; 95%CI, 0.77 to 0.90,P<0.001). Tiotropium also increased the time to the first moderate exacerbations (HR 0.86, 95%CI 0.79 to 0.93, P<0.001) and time to first severe exacerbation (HR 0.72, 95%CI, 0.61 to 0.85; P<0.001).

Tiotropium reduced the total annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89, 95%CI, 0.83 to 0.96, P=0.002). It also reduced the rate of moderate exacerbations (0.54 vs. 0.59, rate ratio 0.93, 95%CI 0.86 to 1.00, P=0.048) and severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95%CI, 0.66 to 0.82; P<0.001) considered separately. The proportion of patients who experienced an exacerbation of either type was 34.4% in the tiotropium group compared to 38.5% in the salmeterol group (NNT 24). The proportions of people with a moderate exacerbation were 30.1% and 32.9% respectively (NNT 36), and the proportions of people with a severe exacerbation were 7.1% and 9.2% respectively (NNT 48). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group.

Study sponsorship Funded by Boehringer Ingelheim and Pfizer.

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