“A once-a-day pill may be better than an inhaler at combating asthma,” according to the Daily Mail. The newspaper said the tablet could free patients from dependence on inhalers and “revolutionise treatment for the condition”.
The pills in question, called leukotriene receptor antagonists, or LTRA tablets, were tested in two trials in 650 patients that compared the drugs to inhaled treatments, both as an initial treatment for newly diagnosed asthma and for asthma that could not be controlled with a single inhaler.
Researchers found in both circumstances that all treatments produced a similar (equivalent) improvement on patients’ quality of life in the initial months of treatment. However, after two years, the quality of life scores were slightly higher in those using inhalers. This means that the tablets did not show better performance than inhalers, as many news sources have reported. The researchers did, however, find that people found it easier to use tablets than inhalers.
LTRA tablets have been available for some years, and this study looked to test their use in a real-world setting rather than under the strictly controlled conditions of an experimental trial. As such, the research can help inform us about factors such as patient’s adherence to their medication, but means that only limited conclusions can be drawn from its results.
LTRA tablets have their uses, just as inhalers do, and doctors can prescribe them when appropriate for an individual patient. However, the results of this research do not support the newspapers’ view that the pills are a better option for most patients.
Where did the story come from?
The study was carried out by researchers from a number of academic institutions in the UK and at McMaster University, Canada. It was funded by the UK’s Health Technology Assessment Programme; Clement Clark International; Research in Real Life Ltd, and grants from the pharmaceutical companies AstraZeneca and Merck Sharp and Dohme. The study was published in the peer-reviewed New England Journal of Medicine.
The study was reported uncritically in the papers, which seemed to use an accompanying press release as the basis for their articles. The Daily Mail’s headline said that pills were more effective than inhalers, a claim not supported by this research. The Mail also referred to the pill as a potential 'wonder drug' despite it performing no better than an inhaler.
What kind of research was this?
This research comprised two separate pragmatic randomised controlled trials, designed to evaluate the effectiveness of LTRA tablets for treating the asthma of patients under the care of their GPs, in what the researchers say are real-world conditions. A pragmatic trial is a randomised trial designed to reflect a drug’s performance when used in normal clinical practice, as opposed to looking at the effectiveness of a drug in the ideal, highly regulated conditions of an experimental trial. The patients selected for a pragmatic study will also reflect those found in any normal clinical practice rather than being drawn from a specifically defined population.
Pragmatic trials can be useful for looking at whether patients adhere to treatments (the ability to keep taking the treatment), although they do have drawbacks that can affect their results. These include their use of a mixed-patient population, the absence of a placebo group for comparison and a lack of blinding, which is the process of preventing researchers and patients from knowing which treatment they are getting.
The two trials looked at whether the performance of LTRA tablets was equivalent to that of treatment with inhalers. The first trial compared the tablets with inhaled steroids in patients who were beginning asthma therapy and the second compared LTRA tablets and LABA inhalers as add-on therapies to inhaled steroids. The researchers’ hypothesis was that initial treatment with LTRA or using it as an addition to steroid inhalers, would lead to improvements in ‘quality of life’ (a patient-oriented measure of effectiveness) and that it would be equivalent to the alternative treatments tested.
The researchers point out that while double-blind randomised controlled trials are the bedrock of evidence in determining a treatment’s effectiveness, they do not guarantee a particular treatment will be effective in clinical practice. In the case of asthma treatments, this effectiveness is often influenced by how easy a treatment is to take and what type of technique patients prefer.
The researchers also point out that current asthma treatment guidelines recommend inhaled steroids as the first line treatment in managing chronic asthma, with the option of an additional LTRA or an add-on inhaler (LABA) if needed. Results from clinical trials of the different approaches have been mixed.
What did the research involve?
The two trials were conducted at 53 GP practices in the UK and enrolled 650 patients between the ages of 12 and 80, who had been diagnosed with asthma. Eligible patients completed a validated asthma symptom diary for two weeks before the start of the trial and were also screened and assessed by telephone and in their clinic.
- In the first line 'controller trial', eligible patients had asthma symptoms their doctors considered to need treatment with a new course of asthma therapy. The participants were randomised to take either an inhaled steroid or an LTRA tablet.
- In the add-on therapy trial, patients were already taking inhaled steroids for their asthma (for at least 12 weeks) and had symptoms requiring an increase in therapy. Alongside an inhaled steroid they were randomly assigned either an LABA inhaler or an LTRA tablet.
Other eligibility criteria included evidence of impaired asthma-related quality of life or impaired asthma control, as measured using the Mini Asthma Quality of Life Questionnaire (MiniAQLQ) and the Asthma Control Questionnaire (ACQ).
The effectiveness of the different treatments was primarily defined using MiniAQLQ scores, although the researchers also looked at secondary measurements including ACQ scores and the frequency of asthma exacerbations. Patients who met eligibility criteria completed a validated symptom diary before the start and were screened and assessed regularly by telephone and in the clinic.
The researchers used statistical methods to determine whether the different treatments were equivalent or not. This meant that they had to predefine what level of improvement and difference between treatments should be considered clinically significant. The researchers decided the two therapies are considered equivalent if the two treatments produced a difference of less than 0.3 points in the MiniAQLQ score.
What were the basic results?
In both trials, the average quality of life scores increased by 0.8-1.0 points over a period of two years.
- At two months, differences in the MiniAQLQ scores between the two treatment groups met the researchers’ definition of equivalence (defined as 95% confidence interval [CI] for an adjusted mean difference of 0.3 points in either direction).
- At two years, mean MiniAQLQ scores for the two treatments approached equivalence, with an adjusted mean difference between treatment groups of –0.11 (95% CI, –0.35 to 0.13) in the first-line controller therapy trial and of –0.11 (95% CI, –0.32 to 0.11) in the add-on therapy trial. The confidence interval ranges for these results meant they were just outside the predetermined range for equivalence.
- Exacerbation rates and ACQ scores did not differ significantly between the two groups.
How did the researchers interpret the results?
The researchers say their study results at two months suggest that LTRA pills are as effective as inhaled steroids as a first-line therapy and as effective as LABA as an add-on therapy in this group of patients. However, equivalence was not proved at two years.
The researchers say that their findings suggest there is little difference in ‘real-world effectiveness’ between LTRA pills and inhaled steroids as a first-line treatment and between an LTRA and LABA as an add-on treatment to steroid inhalers.
They note that adherence to tablets was better than it was to other drugs in the trials, with 65% of patients adhering to tablets, compared to 41% for inhaled steroids in the first line trial and 74% versus 46% in the add-on therapy trial.
In the add-on therapy trial, one-quarter of patients in the LTRA tablet group were switched to a LABA inhaler or received it as an add-on.
The LTRA drugs tested in these two studies are not new, as some newspapers have incorrectly reported, and this research has not shown that they perform better than inhaled treatments. Rather, this research is of benefit for helping to compare how the two types of existing treatment might perform in a clinical setting.
This pragmatic trial is useful for providing data on factors such as the adherence rates for the two therapies, although its study design also means there are a number of limitations that must also be considered when interpreting its results:
- As a pragmatic trial it defines how successful treatments are in practice, rather than under the ideal conditions of an experimental trial.
- It did not measure treatment effectiveness against a placebo and the patients were not ‘blinded’ to prevent them knowing which treatment they were allocated.
- The patients were allowed to ‘cross over’ between different treatments during the study, which affects the reliability of the results. Since more patients starting the LTRA treatment switched medications, it could suggest this treatment was less effective or problematic to use.
As with any medication, both inhalers and LTRA tablets can have benefits and drawbacks associated with their use, which doctors will weigh up when choosing a medication for an individual patient.
Anyone who is concerned about the treatments for controlling asthma should not stop taking them but instead go see their doctor to discuss alternatives.
Analysis by Bazian
Edited by NHS Website
Links to the headlines
Daily Mail, 5 May 2011
The Daily Telegraph, 5 May 2011
Daily Mirror, 5 May 2011
The Sun, 5 May 2011
Links to the science
New England Journal of Medicine 2011; 364:1695-1707 May 5 2011