What Is the Role of Tiotropium in Asthma? A Systematic Review With Meta-analysis

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Rodrigo GJ and Castro-Rodriguez JA. "What is the role of tiotropium in asthma?: a systematic review with meta-analysis". Chest. 2015. 147(2):388-396.
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Clinical Question

In patients with varying severities of asthma, does the addition of tiotropium to inhaled corticosteroids (ICS) +/- salmeterol (LABA) result with improved lung function and reduced asthma exacerbations?

Bottom Line

Tiotropium (5μg daily through Respimat device) should be considered as an alternative to LABA or as an add-on to ICS plus LABA in patients who are poorly controlled on current therapy with ICS +/- LABA.

Major Points

(1) In patients with mild to moderate asthma on ICS monotherapy, tiotropium should be considered as an add-on to improve lung function. (2) In patients with moderate asthma on ICS plus LABA, tiotropium may be considered as an alternative to LABA. (3) In patients with severe asthma that is poorly controlled with ICS plus LABA, the addition of tiotropium should be considered to improve asthma control.

Guidelines

The National Heart, Lung and Blood Institute does not currently recommend tiotropium for management of asthma since it has not been studied in the long-term, and it is not FDA-approved for asthma. [1] Other guidelines also do not mention tiotropium for treatment of asthma.

Design

  • Meta-analysis that included 13 randomized, double-blinded, placebo-controlled trials
  • N= 4,966
  • Studies grouped into three treatment protocols
    • Patients with mild to moderate asthma: Tiotropium as add-on to ICS monotherapy
    • Patients with moderate asthma: Tiotropium + ICS vs ICS + LABA
    • Patients with severe asthma: Tiotropium as add-on to ICS + LABA vs ICS + LABA
  • Duration of studies included ranged from 4 weeks up to 52 weeks
  • Analyzed by intention to treat

Population

  • Patients 18-75 years old
  • Patients with mild, moderate, or severe asthma
  • Nonsmokers or former smokers

Inclusion Criteria

  • >12 years old
  • Symptomatic stable asthma (any severity) treated with ICS or ICS + LABA
  • Comparison of inhaled tiotropium with any treatment
  • Primary outcome reporting peak or trough FEV1 and/or morning or evening peak expiratory flow (PEF) rate
  • Secondary outcomes reporting at least one of the following: rescue medication use, asthma symptom-free days/week, quality of life (using Mini-Asthma Quality of Life Questionnaire (AQLQ) total score), asthma control (using Asthma Control Questionnaire 7 (ACQ-7) total score), ACQ-7 responder rate, asthma exacerbations, withdrawals, and safety
  • Randomized controlled-trial with duration ≥4 weeks

Exclusion Criteria

  • Asthma diagnosed after age 40
  • Unstable asthma
  • Asthma not treated with ICS or ICS + LABA
  • Smokers
  • Study duration of <4 weeks
  • Trials that only published an abstract

Baseline Characteristics

  • Mean age: 42 years
  • Mean Baseline FEV1 % Predicted: 64.6%
  • Mean number of randomized patients per trial included: 382
  • Mean duration: 20 weeks
  • Most common severity of asthma studied: moderate (9 trials)
  • Most common primary outcome: FEV1 peak +/- trough (8 trials)
  • Most common dose of tiotropium: tiotropium 5μg Respimat daily

Interventions

  • Tiotropium daily as add-on to ICS vs. patients receiving ICS monotherapy
    • Seven trials included patients with moderate asthma treated with medium dose of ICS, one trial included patients with mild asthma treated with low dose of ICS, and two trials included patients moderate asthma treated with medium to high dose of ICS
  • Tiotropium daily plus ICS vs ICS plus LABA twice daily in patients with moderate asthma
    • In three trials patients were treated with medium dose of ICS, and in one trial patients were treated with medium to high dose of ICS
  • Tiotropium daily as add-on to ICS plus LABA twice daily vs. ICS plus LABA twice daily
    • Three trials included patients with severe asthma treated with high doses of ICS

Outcomes

Comparisons are addition of tiotropium to ICS +/- LABA vs ICS +/- LABA alone.


Primary Outcomes

  • Primary outcomes: peak/trough FEV1, and/or morning/evening peak expiratory flow (PEF) rates
    • Tiotropium as add-on to ICS compared to ICS monotherapy
Significant improvement in morning and evening PEF
mean change from baseline, 22-24 L/min (95% CI 17.71-26.41, P<0.00001 for morning; 95% CI 20.44-29.02, P<0.00001 for evening)
Significant improvement in peak FEV1
mean change from baseline, 150 mL (95% CI 0.11-0.18; P<0.00001)
Significant improvement in trough FEV1
meach change from baseline, 140 mL (95% CI 0.11-0.16; P<0.00001)
    • Tiotropium plus ICS compared to ICS plus LABA
Significant improvement in morning PEF
mean change from baseline, 6.6 L/min (95% CI 1.59-11.74; P=0.01)
No significant difference in evening PEF
mean change from baseline, 3.4 L/min (95% CI -4.85-11.59; P=0.42)
No significant difference in peak FEV1
mean change from baseline, 20 mL (95% CI -0.01-0.05; P=0.21)
No significant difference in trough FEV1
mean change from baseline, 20 mL (95% CI -0.02-0.06; P=0.31)
    • Tiotropium as add-on to ICS plus LABA compared to ICS plus LABA
Significant improvement in morning and evening PEF
mean change from baseline 16-20 L/min (95% CI 7.13-24.79, P=0.0004 for morning; 95% CI 11.86-30.58, P<0.00001 for evening)
Significant improvement in peak FEV1
mean change from baseline, 120 mL (95% CI 0.09-0.16; P=0.00001)
Significant improvement in trough FEV1
mean change from baseline, 80 mL (95% CI 0.04-0.11; P=0.00001)

Secondary Outcomes

  • Secondary outcomes: rescue medication use, asthma symptom-free days/week, quality of life (Mini-Asthma Quality of Life Questionnaire (AQLQ) total score), asthma control (Asthma Control Questionnaire 7 (ACQ-7) total score), ACQ-7 responder rate, asthma exacerbations, withdrawals, and safety
    • Tiotropium as add-on to ICS compared to ICS monotherapy
Significant improvement in AQLQ total score
mean change from baseline 0.07 (95% CI 0.01-0.13; P=0.03)
Significant improvement in ACQ-7 total score
mean change from baseline -0.14 (95% CI -0.19 to -0.09; P=0.00001)
Likelihood of achieving minimal clinically important difference in ACQ-7 score
66.3% vs 60.2% (95% CI 1.02-1.17; P=0.02; NNT=16)
Decrease in number of patients who experienced at least one asthma exacerbation
10.5% vs 13.3% (95% CI 0.57-0.95; P=0.02; NNT=36)
No significant difference in asthma symptom-free days/week
mean change from baseline 0.02 (95% CI 0.01 to -0.04; P=0.20)
No significant difference in total withdrawals
(95% CI 0.33-1.03; P=0.09)
No significant difference in adverse events
34.6% vs 34.6% (95% CI 0.75-1.07; P=0.22)
  • Tiotropium plus ICS compared to ICS plus LABA
LABA group experienced significant reduction in use of rescue medication
-0.2 puffs/day (95% CI 0.04-0.37; P=0.01)
LABA group experienced significant improvement in AQLQ total score
mean change from baseline -0.12 units (95% CI -0.06 to -0.18; P=0.00001)
No significant difference in asthma symptom-free days/week
mean change from baseline -0.05 (95% CI 0.05 to -0.15; P=0.30)
No significant difference in ACQ-7 total score
mean change from baseline 0.00 (95% CI -0.07-0.07; P=0.98)
No significant difference in number of patients who experienced asthma exacerbations
mean change from baseline 1.23 (95% CI 0.83-1.83; P=0.30)
No significant difference in total withdrawals
(95% CI 0.42-1.83; P=0.73)
No significant difference in adverse events
67.6% vs 72.8% (95% CI 0.82-1.28; P=0.84)
    • Tiotropium as add-on to ICS plus LABA compared to ICS plus LABA
Significant improvement in AQLQ total score
mean change from baseline 0.12 (95% CI 0.05-0.18; P=0.003)
Increase in ACQ-7 total score
mean change from baseline -0.20 (95% CI -0.25 to -0.09; P=0.98)
Likelihood of achieving minimal clinically important difference in ACQ-7 score
58.1% vs 45.1% (95% CI 1.13-1.46; P=0.0001; NNT=8)
Decrease in number of patients who experienced at least one asthma exacerbation
18.2% vs 24.0% (95% CI 0.53-0.94; P=0.02; NNT=17)
No significant difference in total withdrawals
(95% CI 0.64-1.44; P=0.85)
No significant difference in adverse events
(95% CI 0.59-1.01; P=0.06)


Adverse Events

The results show no significant increase in adverse events with the addition of tiotropium to ICS +/- LABA therapy.

Criticisms

Most of the studies included had too short of a duration of treatment, which does not allow for a complete assessment of the efficacy and safety with long-term use of tiotropium in asthma.

Funding

Authors reported that no funding was received for this study.

Further Reading

1. Busse, William W. et al. Expert Panel Report 3: Guidelines For The Diagnosis And Management Of Asthma. 3rd ed. Bethesda, MD: National Heart, Lung, and Blood Institute, 2007. Web. 13 Mar. 2015./>

2. Rodrigo, Gustavo J., and José A. Castro-Rodríguez. 'What Is The Role Of Tiotropium In Asthma?'. Chest 147.2 (2015): 388. Web. 13 Mar. 2015.