Key points from the evidence

The content of this evidence summary was up-to-date in March 2015. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Two replicate randomised controlled trials (RCTs; total n=912) of identical design evaluated tiotropium (Spiriva Respimat) in adults with poorly controlled asthma and persistent airflow obstruction who were already treated with an inhaled corticosteroid (ICS) and a long-acting beta-2 agonist (LABA). Tiotropium improved peak and trough forced expired volume in 1 second (FEV1) and lengthened the time to first severe exacerbation compared with placebo. Differences between add-on therapy with tiotropium and placebo in patient-assessed asthma control and quality of life were small and did not meet the threshold for the minimal clinically important difference. There are no RCTs comparing tiotropium with other active treatments or in people with asthma without persistent airflow obstruction.

Regulatory status: In September 2014, Spiriva Respimat received a licence extension for asthma.

Effectiveness

  • After 24 weeks of treatment in 2 RCTs (n=912), tiotropium (Spiriva Respimat) statistically significantly improved peak and trough FEV1 compared with placebo in adults with poorly controlled asthma despite ICS plus LABA therapy.

  • In the same RCTs, over 48 weeks tiotropium (Spiriva Respimat) delayed the time to severe asthma exacerbation by 56 days (p=0.03) compared with placebo.

Safety

  • The summary of product characteristics states that Spiriva Respimat should be used with caution in people with recent myocardial infarction (within 6 months); any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia needing intervention or a change in drug therapy in the past year; or hospitalised for heart failure (NYHA class III or IV) within the past year. Dry mouth has been reported as a common adverse effect.

  • Spiriva Respimat should not be used as first-line monotherapy for asthma, for the initial treatment of acute episodes of bronchospasm, or for the relief of acute symptoms.

  • The efficacy and safety of Spiriva Respimat in children and adolescents has not yet been established.

  • In two 48-week RCTs (n=912), adverse events assessed as drug-related occurred in 5.7% of people who had tiotropium and 4.6% of those who had placebo (in addition to ICS plus LABA therapy).

Patient factors

  • People in the 2 RCTs had asthma with persistent airway obstruction, with FEV1 and FEV1/ forced vital capacity (FVC) ratios equivalent to those for people with moderate chronic obstructive pulmonary disease (COPD).

  • Tiotropium is only licensed for use in asthma when delivered using the solution for inhalation device, Respimat.

  • Tiotropium is taken once-daily.

Resource implications

  • Spiriva Respimat costs £33.50 for 30 days of treatment.

  • Increasing from moderate to high dose steroid using an ICS/LABA combination product costs between £5.92 and £38.00 for 30 days.

  • Cost of alternative treatments ranges from £2.36 to £17.84.

Update

The following information has become available since this ESNM was produced.

March 2015: Tiotropium delivered via Respimat compared with Handihaler: no significant difference in mortality in TIOSPIR trial

The Medicines and Healthcare Products Regulatory Agency has advised that the risk of cardiovascular side effects should be taken into account when prescribing tiotropium delivered via Respimat or Handihaler to patients with certain cardiac conditions, who were excluded from clinical trials of tiotropium (including TIOSPIR). See Drug Safety Update February 2015 for more information.

Introduction and current guidance

The British guideline on the management of asthma (SIGN guideline 141) recommends a stepwise approach for treating asthma, with ICS as the first-choice regular preventer therapy for adults and children. In adults, if asthma is not adequately controlled using an ICS alone (step 2) the addition of a LABA should be considered (step 3).

If poor control persists despite treatment with moderate dose of ICS and a LABA, treatment options include increasing the dose of ICS (up to 2000 micrograms of beclometasone dipropionate daily) or adding a fourth drug (a leukotriene receptor antagonist, theophylline modified-release or a slow-release beta2 agonist tablet). The guideline states that there are few clinical trials in this specific patient group to guide management, and recommendations are largely based on extrapolation from trials of add-on therapy to ICS alone.

The British guideline on the management of asthma also 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 also appear to be benefit in adding tiotropium to ICS and salmeterol in patients who remain symptomatic despite these medications."

Full text of introduction and current guidance.

Product overview

Tiotropium (Spiriva Respimat, Boehringer Ingelheim Limited) is the first long-acting muscarinic antagonist (LAMA) to be licensed for use in asthma. It is licensed as an add-on maintenance bronchodilator treatment in adults with asthma who are currently treated with the maintenance combination of ICS (at least 800 micrograms of budesonide per day or equivalent) and LABA and who experienced 1 or more severe exacerbations in the previous year.

Full text of product overview.

Evidence review

  • This evidence summary focuses on 2 replicate RCTs of identical design reported by Kerstjens et al. (2012) that compared tiotropium (delivered using the Respimat device) with placebo in adults whose asthma was poorly controlled despite treatment with an ICS plus a LABA.

  • The 2 RCTs included 912 adults (mean age 53 years) with poor asthma control despite treatment with at least 800 micrograms of budesonide or equivalent (median dose 800 micrograms) and a LABA. Participants were required to have an Asthma Control Questionnaire 7 score of 1.5 or higher (suggestive of poor control) and have had at least 1 asthma exacerbation that needed oral corticosteroids in the past year. People with diagnosed COPD and people who had recently smoked were excluded from the trials, although participants were required to have persistent airflow obstruction, defined as a post-bronchodilator FEV1 of 80% or less of the predicted value and 70% or less of forced vital capacity (FVC). Participants were randomised to tiotropium 5 micrograms daily (2 puffs delivered using the Respimat device) or placebo.

  • The 3 primary end points were peak and trough FEV1 at 24 weeks and the time to first severe exacerbation (deterioration needing initiation or doubling of oral corticosteroids for at least 3 days) measured over 48 weeks.

  • At 24 weeks, tiotropium increased peak FEV1 compared with placebo, with a mean difference of 0.086 litres (95% confidence interval [CI] 0.020 to 0.152, p=0.01) in trial 1 and 0.154 litres (95% CI 0.091 to 0.217, p<0.001) in trial 2. Tiotropium also increased trough FEV1, mean difference compared with placebo of 0.088 litres (95% CI 0.027 to 0.149, p=0.01) in trial 1 and 0.111 litres (95%CI 0.053 to 0.169, p<0.001) in trial 2. Pooled data from both studies across 48 weeks showed that the time to first severe exacerbation for 25% of each group was increased by 56 days with tiotropium compared with placebo (282 days compared with 226 days, hazard ratio [HR] 0.79, 95% CI 0.62 to 1.00, p=0.03). In the tiotropium group, 122 out of 453 people (26.9%) had at least 1 severe exacerbation, compared with 149 out of 454 people (32.8%) in the placebo group (OR 0.75, p<0.05).

  • Other patient-oriented outcomes were included as secondary end points. Asthma control was assessed using the Asthma Control Questionnaire 7 and quality of life using the Asthma Quality of Life Questionnaire (both patient-assessed questionnaires). The difference between groups was small on both these questionnaires, was only statistically significant in 1 trial, and did not achieve the minimal clinically important differences (0.5 points on both questionnaires) in either trial.

  • There are no published RCTs directly comparing tiotropium, used within its licensed indication for asthma, with other active treatments.

  • In the two 48-week RCTs (n=912), adverse events attributed to being drug-related were reported in 5.7% of people taking tiotropium and 4.6% of people taking placebo.

Full text of evidence review.

Context

Tiotropium (Spiriva Respimat) is licensed for use in adults with poorly controlled asthma who are currently treated with ICS (at least 800 micrograms of budesonide per day or equivalent) and a LABA. This would place it at step 4 of the British guideline on the management of asthma adult treatment pathway. The British guideline recommends that the following treatment options should be considered at step 4 for adults:

  • increase ICS dose up to the equivalent of 2000 micrograms beclometasone dipropionate per day or equivalent

  • add a leukotriene receptor antagonist (montelukast or zafirlukast)

  • add theophylline modified release

  • add a slow-release beta2 agonist tablet (salbutamol).

Full text of context.

Estimated impact for the NHS

People in the 2 RCTs supporting the licence extension for tiotropium in asthma had persistent airway obstruction, with FEV1 and FEV1/FVC ratios similar to those in people with moderate COPD. The benefit of adding tiotropium to existing ICS and LABA in people without persistent airflow obstruction has not been demonstrated in a published RCT.

It is not known how the efficacy of tiotropium as add-on therapy compares with other active treatments recommended at step 4 of the British guideline on the management of asthma.

Tiotropium is only licensed for use in asthma when delivered using the solution for inhalation device, Respimat. Spiriva Respimat should be used with caution in people with recent myocardial infarction within the past 6 months; any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia needing intervention or a change in drug therapy in the past year; or people who were hospitalised for heart failure (NYHA class III or IV) within the past year. Spiriva Respimat should not be used as first-line monotherapy for asthma or for the initial treatment of acute episodes of bronchospasm, or for the relief of acute symptoms.

The efficacy and safety of Spiriva Respimat in children and adolescents has not yet been established.

Local decision makers will need to consider the available evidence on efficacy and safety, as well as cost and individual patient factors, when making decisions about using tiotropium for treating asthma in adults.

Full text of estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.