A blog for clinicians written by Lynda Ware, giving an overview of four recent Cochrane reviews assessing the effectiveness of LAMAs in asthma care.
In the UK 5.4 million people are receiving treatment for asthma. This equates to 1:11 children and 1:12 adults. In 2014 1216 people died from asthma, or, put another way, about 3 people every day. In addition, a patient was hospitalised every 8 minutes as a result of asthma. The cost to the NHS is around £1billion pounds per year. All this is happening despite our greatly improved understanding of the disease and of its treatment.
Long-acting muscarinic antagonists (LAMAs) are known to be effective in chronic obstructive pulmonary disease and this suite of four Cochrane systematic reviews considers whether they have a role in asthma management. LAMAs are not a named add-on therapy in the BTS/SIGN October 2014 guidelines for the stepwise management of asthma in adults, despite Spiriva (tiotropium) Respimat receiving a licence for the treatment of severe asthma in September 2014, the first new class of inhaled treatment for asthma in over a decade.
What did the Cochrane reviews examine?
The reviews looked at trials in which LAMAs were added to existing preventative therapy in adults with poorly controlled asthma.
The comparisons were:
- LAMA + ICS versus same dose ICS
- LAMA + ICS versus higher dose ICS
- LAMA + ICS versus LABA + ICS
- LAMA + LABA/ICS versus LABA/ICS
where LAMA = long-acting muscarinic antagonist; ICS = inhaled corticosteroid; LABA = long-acting beta2 agonist
What were the outcomes?
The primary outcomes across all the reviews were:
- exacerbations requiring oral corticosteroids
- asthma-related quality of life
- serious all-cause adverse events
And the secondary outcomes were:
- exacerbations requiring hospital admission
- lung function
- asthma control
- any adverse events
Which LAMAs were used in the trials?
The LAMA used in all the trials was tiotropium, most often in the form of a Respimat inhaler. One trial in the LAMA + LABA/ICS vs LABA/ICS review investigated glycopyronium. This trial did not get as far as participant recruitment because the drug was withdrawn.
What were the results?
- The addition of LAMA to ICS resulted in fewer exacerbations requiring oral corticosteroid rescue medication compared to same dose ICS alone. In this comparison, LAMA add-on also improved trough FEV1 by around 140ml. (High The certainty (or quality) of evidence is the extent to which we can be confident that what the research tells us about a particular treatment effect is likely to be accurate. Concerns about factors such as bias can reduce the certainty of the evidence. Evidence may be of high certainty; moderate certainty; low certainty or very-low certainty. Cochrane has adopted the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) for assessing certainty (or quality) of evidence. Find out more here: https://training.cochrane.org/grade-approach More)
- Only one trial was found looking at LAMA add-on to ICS compared to increasing the dose of ICS. LAMA add-on produced a small increase in FEV1 but otherwise the differences between the treatments were too small or imprecise to be sure whether this equated to a safer, more effective treatment. (Moderate quality of evidence)
- Comparing LAMA to LABA as add-ons to ICS, adding LAMA resulted in small benefits to lung function. Asthma-related quality of life measurements were slightly better with LABA add-on. (Moderate-high quality of evidence)
- Small benefits were observed in the comparison of LAMA add-on to LABA/ ICS compared to LABA/ICS alone in lung function and asthma control. There were fewer non-serious adverse events. LAMA add-on may reduce the need for rescue oral steroids but the effect was imprecise.(Moderate – high quality of evidence)
It was the case, however, that for many outcomes the evidence was inconclusive or imprecise or the differences were too small to confidently draw any conclusions.
What does this mean in practice?
Tiotropium appears be beneficial in the treatment of poorly-controlled asthma in adults but it is not clear where it will be assigned a place in the biennial BTS/SIGN asthma guidelines due out in October 2016.
The current British guideline on the management of asthma states that :
“long-acting muscarinic antagonists appear to be as effective as salmeterol in the short term and may be superior to doubling the dose of ICS in fixed airways obstruction. Longer term studies are required to confirm this evidence. There would appear to be benefit in adding tiotropium to ICS and salmeterol in patients who remain symptomatic despite these medications.”
Hopefully further high quality evidence will emerge from ongoing and planned trials to determine where LAMAs have their place in asthma management.
The NICE Evidence Summary New Medicines on tiotropium add-on for asthma is available here https://www.nice.org.uk/advice/esnm55/chapter/Key-points-from-the-evidence
Are long-acting muscarinic antagonists (LAMAs) effective in adults with poorly controlled asthma? by Lynda Ware is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License.
Based on a work at http://www.cochranelibrary.com. The featured image was purchased for Evidently Cochrane from istock.com and may not be reproduced.
Kew KM, Dahri K. Long-acting muscarinic antagonists (LAMA) added to combination long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma. Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD011721. DOI: 10.1002/14651858.CD011721.pub2(http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011721.pub2/abstract)
Anderson DE, Kew KM, Boyter AC. Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus the same dose of ICS alone for adults with asthma. Cochrane Database of Systematic Reviews 2015, Issue 8. Art. No.: CD011397. DOI: 10.1002/14651858.CD011397.pub2(http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011397.pub2/abstract)
Evans DJW, Kew KM, Anderson DE, Boyter AC. Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus higher dose ICS for adults with asthma. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD011437. DOI: 10.1002/14651858.CD011437.pub2.(http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011437.pub2/abstract)
Kew KM, Evans DJW, Allison DE, Boyter AC. Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus addition of long-acting beta2-agonists (LABA) for adults with asthma. Cochrane Database of Systematic Reviews 2015, Issue 6. Art. No.: CD011438. DOI: 10.1002/14651858.CD011438.pub2.(http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011438.pub2/abstract)
Scottish Intercollegiate Guidelines Network (SIGN) and British Thoracic Society. British guideline on the management of asthma. Edinburgh: SIGN; 2014. (SIGN publication no. 141). [October 2014]. Available from URL: http://www.sign.ac.uk/pdf/SIGN141.pdf
National Institute for Health and Care Excellence. Asthma: tiotropium (Spiriva Respimat). (Evidence Summary New Medicines 55). London: National Institute for Health and Care Excellence; 2015, March. Available from:https://www.nice.org.uk/advice/esnm55/chapter/Full-evidence-summary