11 November 2010
A US exploratory study in 210 patients examined the effects of tiotropium in poorly controlled asthma. While hypothesis generating, the study does not provide grounds for clinicians to include tiotropium in their management of people with asthma. The interesting questions raised need to be explored in larger studies of longer duration, as certain methodological problems with this study further limit the conclusions that can be drawn from it.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Tiotropium is currently not a licensed or recommended option for the management of asthma. Health professionals should follow the BTS/SIGN guideline on the management of asthma. Before adding or changing treatment, practitioners should check concordance with existing therapy, check the patient’s inhaler technique and seek to eliminate trigger factors.
What is the background to this?
An earlier Cochrane Review concluded that there was no justification for routinely introducing anticholinergics as part of add-on treatment for patients whose asthma is not well controlled on standard therapies. Although the review mainly focused on the short-acting agent, ipratropium, it also concluded that the role of long-acting muscarinic antagonists (LAMAs), such as tiotropium, has yet to be established in patients with asthma. Tiotropium is currently licensed in the management of COPD, but is not currently approved for treating asthma.
What questions did this study address and how was it designed?
This study was included 210 patients with asthma which was inadequately controlled after a four-week run-in period on beclometasone Qvar 160micrograms each day. Note that the BTS/SIGN guideline states that 200-300micrograms per day of beclometasone Qvar is approximately equivalent to 400micrograms/day of beclometasone given via CFC metered dose inhaler. It was designed to answer two questions:
- Firstly, is adding tiotropium 18micrograms daily to the existing ICS regimen better than doubling the dose of ICS?
- Secondly, is adding tiotropium 18micrograms daily to the existing ICS regimen at least no worse than adding salmeterol 50micrograms twice daily?
The first test was the usual superiority type of study, but the second test was a non-inferiority study. This is a design with which readers may be less familiar but which is discussed below. In addition, the study had a complex, three-way crossover design (see study details, below).
The primary outcome of the study involved the disease-oriented outcome of changes in peak expiratory flow (PEF). Some secondary outcomes measured patient-oriented outcomes such as the number of asthma control days and quality of life measures.
What does this study claim?
Adding tiotropium to the ICS was superior to doubling the dose with regard to the primary outcome: it produced a greater mean change from baseline in morning PEF: 25.8L/min (95% confidence interval [CI] 14.4 to 37.1, P<0.001); baseline morning PEF was 377.2L/min. It was also superior in regard to most secondary outcomes including the proportion of asthma control days, daily symptom scores and score on the Asthma Control Questionnaire (see study details, below).
Adding tiotropium to the ICS was not inferior to adding salmeterol to the ICS, in terms of the predefined criteria of difference in change from baseline in PEF, proportion of asthma-controlled days and pre-bronchodilator FEV1. See below for an interpretation of this result.
The question for practitioners and their patients is – would someone with asthma which is poorly controlled on ICS be better off using a LABA, as in current guidance, or tiotropium? This is only partly addressed by the non-inferiority analysis presented here. Non-inferiority studies such as this need careful critical appraisal. For some readers, it may be enough to know that this is not a study to change practice. It raises interesting questions but further research on larger numbers of patients for longer periods will be needed to judge the place of tiotropium in the care of adults with uncontrolled asthma. For those who wish to know more, a brief critical appraisal is given below.
Unlike the more commonly encountered superiority studies, the design of non-inferiority studies involves setting an acceptable upper limit for the confidence interval for the observed difference between the two treatments being considered. In this case, the authors decided that if the observed upper 97.5% confidence interval for the difference in change from baseline for all the following outcomes was less than the value given, tiotropium would be judged non-inferior to (i.e. not clinically worse than) salmeterol:
- morning PEF upper 97.5%CI less than 10.6L/min
- proportion of asthma-control days less than 0.07 (7% absolute difference)
- pre-bronchodilator FEV1 less than 0.09L
Note that establishing non-inferiority is not quite the same as establishing equivalence and not at all the same as establishing superiority.
The rationale for these criteria is not given in the study report. In addition, the authors state that analyses were performed on the basis of intention-to-treat. However, the EMA states that non-inferiority studies should also be analysed on a per-protocol basis. Non-inferiority can be established only if both analyses support the finding (see a previous rapid review for an explanation and further discussion).
Three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma over a 14-week treatment period.
Patients were assigned to the study if their asthma was inadequately controlled after a four-week run-in period on low dose beclometasone (two puffs of 40micrograms beclometasone Qvar, twice daily). Patients were considered to be inadequately controlled if the forced expiratory volume in 1 second (FEV1) was 70% or less of the predicted value or if during the final two weeks of the run-in period they had symptoms six or more days per week or used a rescue inhaler six or more days per week or were awakened by symptoms of asthma two nights or more per week.
Intervention and comparison:
Patients were separated into three streams and each stream was treated over 14-week periods with the run-in dose of beclomethasone (80micrograms twice daily) plus:
- inhaled tiotropium bromide (Spiriva® HandiHaler) 18micrograms every morning plus a salmeterol placebo inhaler; or
- 160micrograms (2 puffs of 80micrograms) twice daily of beclometasone (i.e., a doubling of the run-in dose) plus a tiotropium placebo inhaler and salmeterol placebo inhaler; or
- salmeterol xinafoate (Serevent Diskus®) at a dose of 50micrograms twice daily plus a tiotropium placebo inhaler.
All three streams of patients were rotated through each of the treatment regimens outlined above. Between each treatment period there was a 2-week washout period during which patients received only the run-in dose of beclometasone to establish baseline data for the next period.
Outcomes and results:
Superiority study (vs. doubling dose of ICS):
- Primary outcome: mean difference in mean change from baseline in morning PEF = 25.8 litres per minute (95%CI 14.4 to 37.1, P<0.001).
- Tiotropium was also found to be superior in most secondary outcomes, including:
— Evening PEF, difference in change from baseline 35.3L/min (95%CI 24.6 to 46.0, P<0.001);
— Proportion of asthma control days, difference in change from baseline 0.079 (95%CI 0.019 to 0.140, P = 0.01);
— Pre-bronchodilator FEV1 difference in change from baseline 0.10L (95%CI 0.03 to 0.17, P = 0.004);
— Daily symptom scores, difference in change from baseline −0.11 points (95%CI -0.16 to 0.06, P<0.001);
— Score on the Asthma Control Questionnaire, difference in change from baseline -0.18 points (95%CI -0.34 to -0.03, P=0.02);
— Post-bronchodilator FEV1 after four puffs of salbutamol, difference in change from baseline of 0.04 litres (95%CI 0.01 to 0.08, P=0.01)
Non-inferiority study (vs. salmeterol)
- Tiotropium met the predefined criteria for non-inferiority:
— Morning PEF, difference in change from baseline 6.4L/min (95%CI -4.8 to 17.5; P=0.26)
— Proportion of asthma control days, difference in change from baseline −0.009 (95% CI −0.070 to 0.053; P=0.78);
— Prebronchodilator FEV1 difference in change from baseline 0.11L (95% CI 0.04 to 0.18; P=0.003);
This study was supported by grants from the US National Heart, Lung, and Blood Institute
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