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4 November 2009
A short-term randomised controlled trial claims benefits for the addition of inhaled budesonide/formoterol to tiotropium (i.e. triple vs. single therapy) in patients with COPD. However, limitations of the study question its validity and relevance to clinical practice.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Action
Healthcare professionals should not change practice on the basis of this study, and should continue to use inhaled therapy for symptom relief in patients with COPD in accordance with NICE guidance.
According to NICE guidance, breathlessness and exercise limitation should be treated initially with a short-acting bronchodilator (beta2-agonist or anticholinergic) as needed. If this does not control symptoms then a long-acting bronchodilator (tiotropium or long-acting beta2-agonist [LABA]) should be prescribed (a combination of a short-acting beta2-agonist and a short-acting anticholinergic before this step is an option in the guideline). A long-acting bronchodilator should also be prescribed if the patient has two or more exacerbations a year. An inhaled corticosteroid (ICS) should be prescribed in addition for patients with a forced expiratory volume in one second (FEV1) of 50% predicted or less, and who have two or more exacerbations needing treatment with antibiotics or oral corticosteroids a year.
If patients remain symptomatic on monotherapy, their treatment should be intensified by combining therapies from different drug classes. Effective combinations include: beta2-agonist and anticholinergic; beta2-agonist and theophylline; anticholinergic and theophylline; LABA and ICS. In patients with moderate or severe COPD who are still symptomatic a combination of LABA/ICS is suggested but should be discontinued if no benefit is seen after four weeks.
What is the background to this?
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 have frequent exacerbations. Few studies have investigated the effect of triple therapy with tiotropium, LABA and ICS compared with other therapies. A one-year study of 449 patients with moderate or severe COPD, which found that adding salmeterol or salmeterol/fluticasone to tiotropium did not reduce exacerbations in people with moderate to severe COPD. However, some statistically significant improvements in secondary outcomes (lung function, quality of life, and hospitalisation rates) were found. The present study aimed to assess the efficacy and tolerability of budesonide/formoterol added to tiotropium in patients eligible for LABA/ICS therapy.
What does this study claim?
The authors claim, on the basis of this study, that budesonide/formoterol added to tiotropium provides rapid and sustained improvements with regard to lung function, improved morning symptoms and activities, and reduces severe exacerbations, compared with tiotropium alone.
With regard to the primary outcome, the study identified a statistically significant improvement in FEV1 of 65ml (1.25 vs. 1.08L; relative risk (RR) 1.06, 95% confidence interval [CI] 1.04 to 1.09; P<0.001) from pre-dose baseline over 12 weeks for patients receiving budesonide/formoterol compared with those receiving placebo (both added to tiotropium).
The study identified some other statistically significant improvements for triple therapy over monotherapy for some secondary outcomes. For example, there was a reduction in the in the rate of severe exacerbations (defined as worsening of COPD leading to treatment with systemic corticosteroids and/or hospitalisation/emergency room visit) from 18.5% to 7.6% (RR 0.38; 95%CI 0.25 to 0.57; P<0.001). Health related quality of life, assessed with the St. George’s Respiratory Questionnaire for COPD (SGRQ-C) was also improved more in the triple therapy group than in the monotherapy group (3.8 units vs. 1.5 units; difference 2.3, 95%CI 0.32 to 4.23; P=0.023).
So what?
The study suggests possible benefits of adding budesonide/formoterol to tiotropium in patients with COPD. However, it is important to consider several limitations of the study that question its validity and relevance to currently recommended clinical practice in the UK.
The most obvious limitation in the study is its basic design. The study compared triple therapy to monotherapy therapy. It provides no useful information on the benefits of dual therapy (i.e. adding either of the individual components of budesonide/formoterol inhaler to tiotropium) and it is impossible to tell how much each of the components contributed to the benefits seen. The reason for not including the additional arm(s) into the study to provide this information is not clear. We do not know whether the patients who benefited from the added combination would have done better (or indeed worse) if budesonide or formoterol alone had been added to tiotropium. The earlier study of triple therapy using add-on fluticasone/salmeterol was much more robust, in terms of its duration (one year vs. 12 weeks) and the inclusion of a dual therapy arm with salmeterol and tiotropium. This earlier study found no difference in the exacerbation rate between triple therapy and either mono or dual therapy.
The study’s stated objective was to investigate the effect of adding budesonide/formoterol to tiotropium to patients eligible for ICS/LABA combination therapy. From a UK perspective, if we consider the NICE guidance, addition of long-acting inhaled bronchodilators (LABA and/or tiotropium) should be used to control symptoms and improve exercise capacity in patients who continue to experience problems despite the use of short-acting drugs. Addition of a LABA to tiotropium can also be considered if the patient is experiencing two or more exacerbations a year. An ICS should be added to long-acting bronchodilators to decrease exacerbation frequency in patients with an FEV1 less than or equal to 50% predicted who have had two or more exacerbations requiring treatment with antibiotics or oral corticosteroids per year. The inclusion criteria for exacerbations in the present study (at least one COPD exacerbation requiring antibiotics or systemic steroids) and the mean number of exacerbations in patients at baseline (1.4 per year) appears to fall short of NICE recommendations for addition of an ICS.
Examination of treatments used by patients at the time of study entry reveals a wide range of treatment regimens being used previously. About half were receiving a long-acting muscarinic (tiotropium) before entering the study, whereas two thirds were already receiving ICS and three-quarters were receiving a LABA; many were clearly already receiving combination therapy. It would seem that for most cases the window of opportunity for assessing the benefits of adding a LABA or an ICS to tiotropium had already been passed for most of the patients.
The design called for patients to be withdrawn from their ICS/LABA therapy prior to a two-week run-in period, when they were given tiotropium (and reliever therapy) only before randomisation. Perhaps it is not surprising that reintroduction of ICS and or LABA, which many patients had already been receiving to control their symptoms before entering the study, provided some benefit. Despite this limitation, the degree of improvement in lung function was small, and as pointed out in the Editorial, not sufficient to reach the level normally considered to be clinically significant. This also applies to the small degree of improvement in health-related quality of life.
The study can be criticised for use of some unvalidated scoring systems for evaluating exacerbations. The Editorial identified that the definition of severe exacerbation used for this study differed from that of other studies because it included hospital/emergency room visits (regardless of whether or not they required antibiotic/systemic corticosteroid treatment). It points out that there was no significant difference between triple and monotherapy regarding antibiotic-treated exacerbations and the rate of corticosteroid-treated exacerbations was not reported. The results can not therefore be compared directly with other studies in this respect.
The study was of too short a duration (only 12 weeks) to provide meaningful information on long-term clinical outcomes; longer term studies are required to substantiate the apparent benefits in outcomes and adverse effects. The EMEA recommends that pivotal clinical studies in COPD should be longer than six months in duration. Although this study was only of 12 weeks duration, it took place over an entire year, and many of the subjects would have been treated and evaluated outside of the winter period when exacerbations and pneumonia are more likely. The potential of the study to demonstrate clinically meaningful improvements in these parameters was, therefore, diluted considerably.
Another limitation of the study is the failure to provide the reasoning behind the estimation of the sample numbers for the study (power calculation). No justification is given for why a 6% reduction in FEV1 (the actual difference shown in the study) was chosen as being a clinically meaningful level on which to power a study to show superiority of one therapy over another. Furthermore, no explanation of the choice of expected variation in response (i.e. standard deviation) used in the power calculation is provided. We have discussed inadequate sample size calculation and reporting in clinical trials in a previous Blog.
The large number of centres used in the study, with an average of only about 6 subjects per centre might indicate a seeding trial (see previous Blog).
More information on COPD can be found in a recent MeReC Bulletin and on the COPD section of NPC.
Study details
Design: Multicentre (102 centres, 9 countries), double-blind, randomised controlled trial. Enrollment started May 2007 and the last subject completed in June 2008.
Patients: 660 patients (75% male); mean age 62 years; mean FEV1 38% predicted normal (25% FEV1 50 to 80%, 11% FEV1 less than 30% predicted); mean exacerbations during the last year 1.4.
Intervention and comparison: Previous treatments with LABA and/or ICS were withdrawn 2 and 4 weeks, respectively, before a 2 week run-in phase with tiotropium only. Patients continued to receive tiotropium (18 micrograms daily), and were randomised to receive either combination budesonide/formoterol 320/9 microgram or placebo twice daily for 12 weeks.
Outcomes/results:
The primary outcome was the change in pre-dose FEV1 from baseline. There was a statistically significant improvement in FEV1 of 65ml (1.15 vs. 1.08L; RR 1.06, 95%CI 1.04 to 1.09; P<0.001) from pre-dose baseline over 12 weeks for patients receiving tiotropium plus budesonide/formoterol compared with those receiving tiotropium plus placebo.
Secondary outcomes:
Budesonide/formoterol reduced the rate of severe exacerbations (defined as worsening of COPD leading to treatment with systemic corticosteroids and/or hospitalisation/emergency room visit) compared with placebo from 18.5% to 7.6% (RR 0.38; 95%CI 0.25 to 0.57; P=<0.001).
Health related quality of life, assessed with the St. George’s Respiratory Questionnaire for COPD, was also improved more in the triple therapy group than in the monotherapy group (3.8 units vs. 1.5 units; difference 2.3, 95%CI 0.32 to 4.23).
Compared with placebo, statistically significant treatment differences in favour of triple therapy were seen for all COPD symptoms (including breathlessness, night-time awakening, chest tightness and cough), total morning activity scores, and reliever use, from run-in to last week of treatment (week 12) (all P<0.001).
Adverse events were reported in 25% of patients in both groups, with no apparent difference in adverse event profiles between the groups. There were three cases of pneumonia reported in each treatment group.
Sponsorship: AstraZeneca
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