Does adding tiotropium, a long-acting muscarinic antagonist (LAMA), to combination therapy (LABA/ICS) help to control asthma?

Adding the LAMA tiotropium Respimat inhaler to combination LABA/ICS inhaler may reduce the need for rescue oral steroids. A noticeable benefit on quality of life is unlikely, and we couldn't tell if it reduced hospital admissions, but adding tiotropium has some benefit on lung function, asthma control, and non-serious side effects.

More detail about the studies and results:

Taking a daily inhaler containing a long-acting beta2-agonist and an inhaled corticosteroid (LABA/ICS) can improve symptoms and reduce the likelihood of asthma attacks. If this doesn't help, another type of inhaled drug called a long-acting muscarinic antagonist (LAMA), which has been effective for people with other breathing conditions, is now available for people with asthma to take as well as their LABA/ICS inhaler.

We wanted to find out whether adding a LAMA to LABA/ICS is better than continuing LABA/ICS alone for adults with asthma.

We found four relevant studies, but one was withdrawn before anyone was signed up. The other three compared a LAMA called tiotropium Respimat to placebo for around a year, with participants in both groups continuing to take their usual LABA/ICS inhaler. People generally had quite poor lung function when they entered the studies, suggesting their asthma was not well controlled - in respiratory medicine, this is known as 'severe asthma'.

Over 48 weeks, 328 out of 1000 people taking their usual LABA/ICS had to take a course of oral steroids compared with 271 if they took tiotropium as well. However, uncertainty in the results meant that rather than there being 271 people taking oral steroids, there could be anywhere from 218 to 333 people per 1000 who would have to take oral steroids, so we couldn't be sure of the benefit. Quality of life scores were not that different between those who took tiotropium and those who didn't. The studies showed different results for whether people taking tiotropium were more likely to suffer a serious side effect, but fewer people had non-serious side effects if they took tiotropium.

We couldn't tell whether taking tiotropium on top of LABA/ICS reduced the number of people who had to go to hospital for an asthma attack because it didn't happen often enough for us to have confidence in the result. There was high quality evidence that showed benefits to lung function and probably small benefits on measures of asthma control.

Authors' conclusions: 

Tiotropium add-on may have additional benefits over LABA/ICS alone in reducing the need for rescue oral steroids in people with severe asthma. The effect was imprecise, and there was no evidence for other LAMA preparations. Possible benefits on quality of life were negligible, and evidence for the effect on serious adverse events was inconsistent. There are likely to be small added benefits for tiotropium Respimat 5 µg daily on lung function and asthma control over LABA/ICS alone and fewer non-serious adverse events. The benefit of tiotropium add-on on the frequency of hospital admission is still unknown, despite year-long trials.

Ongoing and future trials should clearly describe participants' background medications to help clinicians judge how the findings relate to stepwise care. If studies test LAMAs other than tiotropium Respimat for asthma, they should be at least six months long and use accepted and validated outcomes to allow comparisons of the safety and effectiveness between different preparations.

Read the full abstract...
Background: 

Maintenance treatment with long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) can relieve asthma symptoms and reduce the frequency of exacerbations, but there are limited treatment options for people who do not gain control on combination LABA/ICS. Long-acting muscarinic antagonists (LAMA) are a class of inhaled drug which have been effective for people with chronic obstructive pulmonary disease and are now becoming available for people with asthma to take alongside their LABA/ICS inhaler.

Objectives: 

To assess the effects of adding a long-acting muscarinic antagonist (LAMA) to combination long-acting beta2-agonists (LABA) and inhaled corticosteroids (ICS) in adults whose asthma is not well controlled by LABA/ICS.

Search strategy: 

We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to January 2016. We also searched ClinicalTrials.gov, the WHO trials portal, and reference lists of other reviews, and we contacted trial authors for additional information.

Selection criteria: 

We included parallel randomised controlled trials (RCTs) of at least 12 weeks' duration. Studies met the inclusion criteria if they compared LAMA as an add-on to LABA/ICS versus LABA/ICS alone for adults with asthma. We included studies reported as full text, those published as abstract only, and unpublished data. Primary outcomes were exacerbations requiring oral corticosteroids (OCS), validated measures of asthma control, and serious adverse events (including mortality).

Data collection and analysis: 

Two review authors screened searches and independently extracted details on risk of bias and numerical data. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MD) using a random-effects model. We rated all outcomes using GRADE.

Main results: 

We found four double-blind, double-dummy trials comparing LAMA to placebo, including 1197 people with asthma taking combination LABA/ICS. One of the trials was designed to study glycopyrronium bromide but was withdrawn prior to enrolment, and the other three all studied tiotropium bromide (mostly 5 µg once daily via Respimat) over 48 to 52 weeks. People in the trials had a mean forced expiratory volume in one second (FEV1) of 55% of their predicted value, indicating severe asthma.

People randomised to take tiotropium add-on had fewer exacerbations requiring oral corticosteroids than those continuing to take LABA/ICS alone, but the confidence intervals did not rule out no difference (OR 0.76, 95% CI 0.57 to 1.02; moderate quality evidence). Over 48 weeks, 328 out of 1000 people taking their usual LABA/ICS would have to take oral corticosteroids for an exacerbation compared with 271 if they took tiotropium as well (95% CI 218 to 333 per 1000). Analyses comparing the number of exacerbations per patient in each group (rate ratio) and the time until first exacerbation (hazard ratio) were in keeping with the main result. Quality of life, as measured by the Asthma Quality of Life Questionnaire (AQLQ) was no better for those taking tiotropium add-on than for those taking LABA/ICS alone when considered in light of the 0.5 minimal clinically important difference on the scale (MD 0.09, 95% CI − 0.03 to 0.20), and evidence for whether tiotropium increased or decreased serious adverse events in this population was inconsistent (OR 0.60, 95% CI 0.24 to 1.47; I2 = 76%).

Within the secondary outcomes, exacerbations requiring hospital admission were too rare to tell whether tiotropium was beneficial over LABA/ICS alone. There was high quality evidence showing benefits to lung function (trough FEV1 and forced vital capacity (FVC)) and potentially small benefits to asthma control. People taking tiotropium add-on were less likely to experience non-serious adverse events.

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