Tiotropium in asthma: a systematic review

Figures & data

Figure 1 Selection process of citations.

Abbreviation: COPD, chronic obstructive pulmonary disease.

Table 1 Design summary of the reviewed articles

Study	Inclusion criteria	Design	Duration	Size	Intervention	Overall conclusion
Bateman et al^Citation22	Inadequately controlled moderate persistent asthma: B16-Arg/Arg patients FEV1 <90% for patients on ICS–LABA or <80% for patients on ICS Reversibility (> 12% and 200 mL ≤10 pack-year smoking	Randomized, double-blind, double-dummy, placebo-controlled, parallel-group	16 weeks	388	Initial 4 weeks: usual ICS dose (400–1,000 μg daily) and 50 μg salmeterol twice daily (run-in) Subsequent 16 weeks: 5 μg tiotropium daily in evening 50 μg salmeterol twice a day Placebo	Tiotropium superior to placebo and noninferior to salmeterol in moderate persistent asthma with B16-Arg/Arg genotype
Fardon et al^Citation19	Severe persistent asthma: FEV1 <65% predicted FVC <80% predicted Reversibility >5% Nonsmokers	Randomized, double-blind, placebo-controlled, crossover	4 weeks	18	Initial 4 weeks: fluticasone 1,000 mcg daily (run-in) Subsequent 4-week crossover periods: Fluticasone 500 μg all patients Salmeterol and placebo Salmeterol and tiotropium	Tiotropium may offer small benefit when added to salmeterol in stepping down ICS with no effect on the quality of life or subjective symptoms
Kerstjens et al^Citation21	Uncontrolled severe persistent asthma: FEV, <80% predicted despite high-dose ICS and LABA ACQ ≥ 1.5 < 10 pack-year smoking	Randomized, double-blind, placebo-controlled, crossover	8 weeks	107	Initial 2 weeks: usual dose of ICS and LABA (screen) Subsequent 8-week crossover periods: Tiotropium 5 mcg in morning Tiotropium 10 mcg in morning Placebo	Tiotropium significantly improved lung function when added to ICS – LABA
Kerstjens et al^Citation23	Inadequately controlled severe persistent asthma: FEV1 ≤80% ACQ ≥1.5 despite high-dose ICS and LABA < 10 pack-year smoking One exacerbation requiring oral CS in previous year	Randomized, double-blind, placebo-controlled, parallel-group	48 weeks	912	Initial 4 weeks: usual ICS (≥800 μg) and LABA (run-in) Subsequent 48 weeks: Tiotropium 5 μg daily in morning Placebo group	Tiotropium improved lung function and reduced exacerbations when added to ICS–LABA
Peters et al^Citation20	Inadequately controlled severe persistent asthma: FEV1 <70% or symptoms >6 days/week or nocturnal symptoms >twice/week < 10 pack-year smoking	Randomized, three-way double-blind, triple-dummy, crossover	14 weeks	210	Initial 4 weeks: ICS 160 μg daily (run-in) Subsequent 14-week crossover periods: Tiotropium 18 μg in morning Salmeterol 50 μg twice daily ICS 320 μg daily (double-dose ICS)	Tiotropium noninferior to salmeterol and superior to double-dose ICS regarding symptoms and lung function

Abbreviations: ACQ, Asthma Control Questionnaire; CS, corticosteroid; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroid; LABA, long-acting inhaled β₂-agonist.

Table 2 Results summary of the reviewed articles

Study	Primary outcome	Secondary outcome	Mode of delivery	Safety
Bateman et al^Citation22	Change in mean weekly predose PEF: Tiotropium: −3.9±4.87 L/min Salmeterol: −3.2±4.64 L/min Placebo: −24.6±4.84 L/min. Tiotropium was superior to placebo (P<0.05) but was noninferior to salmeterol (estimated difference −0.78 L/min, 95% CI: −13.096 to 11.53, P=0.002).	Mean weekly PEF and FEV1 worse in the placebo group; similar between salmeterol and tiotropium (P<0.01). Rescue medication use, limitation of activities, and daytime asthma symptoms maintained in active treatment groups but worsened in the placebo group. Reduction of rescue medication use statistically significant only in the salmeterol group. No evidence of a treatment response in quality of life measures. Number of asthma-free days slightly increased in the tiotropium and salmeterol groups, more than placebo.	Respimat	Adverse events reported by 41.3%, 39.8%, and 41.8% of patients in the placebo, tiotropium, and salmeterol groups, respectively. Individual adverse event reporting generally similar for the three treatment groups. Asthma exacerbations reported in similar rates for the three treatment groups. No cardiovascular events were reported.
Fardon et al^Citation19	Not stated but change in FEV1 and AM PEF emphasized. Significant improvements in AM PEF with salmeterol–ICS (41.5 L/min, P<0.01) and salmeterol–ICS-tiotropium (55.3 L/min, P<0.0l). Significant improvements in FEV1 with salmeterol–ICS-tiotropium (0.17 L, P<0.05) but not salmeterol–ICS. No differences between the two treatments in change in AM PEF or FEV1	Salmeterol slightly superior regarding asthma-free days than tiotropium (1.84 vs 1.34, respectively, 95% CI: −0.955 to −0.069). RV and TLC were not altered by any treatment. Addition of tiotropium to salmeterol–ICS reduced exhaled NO by 2.86 ppb (P<0.05). No changes in quality of life or symptoms.	Metered dose inhaler	Not discussed directly.
Kerstjens et al^Citation21	Peak FEV, within 3 hours after dosing at end of 8-week treatment. 5 μg tiotropium: peak FEV1 significantly higher than placebo (139 mL difference, 95% CI: 96–181 mL). 10μg tiotropium: peak FEV1 significantly higher than placebo (170 mL difference, 95% CI: 128–213 mL). There were no significant differences between active treatments.	Significant differences between 5 μg tiotropium and placebo for trough FEV1 (difference of 86 mL, 95% CI: 41–132 mL) and between 10 μg tiotropium and placebo (difference 113 mL, 95% CI: 67–59 mL). Both treatment doses of tiotropium were superior to placebo in peak FVC, trough FVC, and area under the curve for FVC during the first 3 hours, and weekly AM and PM PEF. The 10 μg dose of tiotropium resulted in significantly better AM and PM PEF than the lower dose. No significant differences in asthma symptoms, use of rescue medications, and change in Mini AQLQ with either dose of tiotropium or placebo.	Respimat	Adverse events in 40%, 42%, and 50% of patients receiving placebo, 5 μg tiotropium, and 10 μg tiotropium, respectively. Dry mouth reported by more patients in the 10 μg tiotropium dose group. Severe adverse events in 5 patients (all nonlife-threatening and nondrug related). No blood pressure, pulse rate, ECG, or laboratory test abnormalities could be attributed to the study drug or dose.
Kerstjens et al^Citation23	Coprimary end points were peak FEV, difference in tiotropium vs placebo after 3 hours of administration and trough FEV1 response at week 24. In both trials there was a superior response to tiotropium compared with placebo for peak FEV, (trial 1 difference of 86±34 mL, P=0.01; trial 2 difference of 154±32 mL, P<0.00l) and trough FEV1 (trial 1 difference of 88±3 1 mL, P=0.01; trial 2 difference of 110±30 mL, P<0.001).	Time to first severe asthma exacerbation increased in the tiotropium group by 56 days, with overall 21% reduction in exacerbations (P=0.03). Small but inconsistent changes with tiotropium compared with placebo in ACQ-7, AQLQ, symptom-free days recorded in the electronic diary, and use of rescue medications.	Respimat	Adverse events reported in 73.5% and 80.3% of patients in the tiotropium and placebo groups, respectively. Serious adverse events reported in 8.1% of patients in the tiotropium group and 8.8% in the placebo group. The only individual adverse event reported in more than 2% of patients and more frequently in the tiotropium group than placebo was allergic rhinitis. Drug-related cardiac events were infrequent (0.4% in the tiotropium group and 0.2% in the placebo group). Blood pressure, pulse rate, and ECG abnormalities were balanced between the two groups. Three life-threatening events occurred in the tiotropium group (2 asthma exacerbations and 1 cerebral infarction) but none with placebo.
Peters et al^Citation20	AM PEF: tiotropium was superior to double dose of ICS (mean difference 25.8 L/min, P<0.00l). Tiotropium was noninferior to salmeterol (difference of 6.4 L/min, P=0.26).	Tiotropium was superior to double dose of ICS for PM PEF (difference of 35.3 L/min, P<0.001), FEV, (difference of 0.10 L, P=0.004), and daily symptom scores (difference −0.1 1 points, P<0.001). Tiotropium was noninferior to salmeterol in other lung function and symptom assessments except for prebronchidilator FEV1 (tiotropium superior with difference of 0.11 L, P=0.003).	HandiHaler	Individual adverse events not reported. Asthma exacerbations occurred in 9 patients on tiotropium, 16 patients on double-dose ICS, and 5 patients on salmeterol. There were 12 serious adverse events, 3 in the tiotropium group, 4 in the double-dose ICS group, and 4 in the salmeterol group.

Abbreviations: ACQ, Asthma Control Questionnaire; AM, morning; AQLQ, Asthma Quality of Life Questionnaire; CI, confidence interval; ECG, electrocardiogram; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroid; NO, nitric oxide; PEF, peak expiratory flow; PM, evening; RV, residual volume; TLC, total lung capacity.

BatemanEDKornamannOSchmidtPTiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthmaJ Allergy Clin Immunol201112831532221807250

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FardonTHaggartKLeeDKLipworthBJA proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotripium in severe persistent asthmaRespir Med20071011218122817178217

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KerstjensHAMDisseBSchroder-BaboWTiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trialJ Allergy Clin Immunol201112830831421636120

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KerstjensHAEngleMDahlRTiotropium in asthma poorly controlled with standard combination therapyNEMJ201236712571259

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PetersSPKunselmanSJIcitovicNTiotropium bromide step-up therapy for adults with uncontrolled asthmaNEMJ201036317151726

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