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Clinical Studies

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TIOSPIR®

Wise RA, Anzueto A, Calverley P, et al. The Tiotropium Safety and Performance in Respimat Trial (TIOSPIR), a large scale, randomized, controlled, parallel-group trial-design and rationale. Respir Res. 2013;14:40. doi: 10.1186/1465-9921-14-40. PubMed PMID: 23547660; PubMed Central PMCID: PMC3621103.

An introduction to the design of the TIOSPIR® study, which provides data on the safety and efficacy of tiotropium delivered via either Respimat® Soft Mist Inhaler or HandiHaler®. The randomised, double-blind, double-dummy, event-driven, parallel-group study includes over 17,000 patients in 50 countries.

Wise RA, Anzueto A, Cotton D, et al; the TIOSPIR Investigators. Tiotropium Respimat® inhaler and the risk of death in COPD. N Engl J Med. 2013;369(16):1491-1501. PubMed PMID: 23992515.

Results of the TIOSPIR® trial comparing SPIRIVA® Respimat® 2.5 μg (two puffs, once daily) and SPIRIVA® 18 μg via HandiHaler® are presented. Results support previous long-term clinical safety and efficacy findings for SPIRIVA® HandiHaler® and show that SPIRIVA® Respimat® and SPIRIVA® HandiHaler® are similar to each other with respect to both safety and efficacy.

POET-COPD®

Vogelmeier C, Hederer B, Glaab T, et al; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-1103. doi: 0.1056/NEJMoa1008378. PubMed PMID: 21428765.

This 1-year, randomised, double-blind, double-dummy, parallel-group trial compared the effect of treatment with tiotropium 18 μg via HandiHaler® once daily with that of salmeterol 50 μg twice daily on the incidence of moderate or severe exacerbations in COPD patients. It was found that in patients with moderate-to-very-severe COPD, tiotropium 18 μg via HandiHaler® is more effective than salmeterol in preventing exacerbations.

Rabe KF, Fabbri LM, Vogelmeier C, et al. Seasonal distribution of COPD exacerbations in the Prevention of Exacerbations with Tiotropium in COPD trial. Chest. 2013;143(3):711-719. PubMed PMID: 23188489.

An analysis of the impact seasons may have on the incidence of COPD exacerbations using data from the POET-COPD® trial. It was found that there is a marked impact of season on outcomes of exacerbations, treatment with antibiotics, timing of further exacerbations and mortality.

Vogelmeier C, Fabbri LM, Rabe KF, et al. Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naïve patients. Respir Med. 2013;107(1):75-83. doi: 10.1016/j.rmed.2012.09.015. Epub 2012 Oct 26. PubMed PMID: 23102611.

Results of pre-specified subgroup analyses from the POET-COPD® study. These analyses report that time to first exacerbation and annual exacerbation rates in moderate COPD and maintenance therapy naïve patients showed a significant benefit for those using tiotropium versus salmeterol. The results support the use of tiotropium 18 μg via HandiHaler® as first-choice maintenance therapy in GOLD stage II COPD patients.

POET-COPD® Subanalysis

Vogelmeier CF, Asijee GM, Kupas K, Beeh KM. Tiotropium and salmererol in COPD patients at risk of exacerbations: a post-hoc analysis from POET-COPD®. Adv Ther. 2015;32:537-547.

In post-hoc analysis of a 1-year, randomised, double-blind, double-dummy, parallel-group trial, the effect of tiotropium 18 µg once daily and salmeterol 50 µg twice daily were analysed on moderate to severe exacerbations in patients with COPD (POET-COPD®). The primary endpoint was time to first moderate or severe exacerbation. Secondary and safety endpoints included time to exacerbation, number of exacerbations, serious adverse events, and mortality. Patients receiving fixed-dose combinations of long-acting beta agonists (LABA) and inhaled corticosteroids (ICS) switched to monotherapy (on equal ICS dose) at the start of randomised treatment. All COPD medications, except for anticholinergics and LABAs were permitted during the double-blind treatment phase. Tiotropium significantly increased time to first COPD exacerbation and reduced the number of COPD exacerbations in high-risk patients. The risk of remaining in the high-risk exacerbator subgroup was statistically lower, and in low-risk patients, time to first COPD exacerbation and number of COPD exacerbations were numerically lower with tiotropium. The risk of transitioning from a low to a high exacerbation risk subgroup was lower with tiotropium versus salmeterol.

Inclusion criteria: Age ≥40 years old, smoking history ≥10 pack years, diagnosis of COPD, and at least 1 exacerbation in the previous year requiring treatment with systemic steroids and/or antibiotics and/or hospitalisation.

Exacerbations were defined as increases, or new onset of, at least 2 respiratory symptoms with at least 1 symptom lasting for 3 or more days and requiring treatment with systemic corticosteroids and/or antibiotics or request hospitalisation.

UPLIFT®

Tashkin DP, Celli B, Senn S, et al; for the UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554. doi: 10.1056/NEJMoa0805800. Epub 2008 Oct 5. PubMed PMID: 18836213.

In this randomised, double-blind trial, 4 years of therapy with either tiotropium 18 μg via HandiHaler® or placebo in patients with COPD was compared. Patients were permitted to use all respiratory medications except inhaled anticholinergic drugs. Therapy with tiotropium 18 μg via HandiHaler® resulted in sustained improvements in lung function, quality of life, and reduction in the risk of exacerbations, and related hospitalisations during a 4-year period but did not significantly reduce the rate of decline in FEV1.

Tashkin DP. Impact of tiotropium on the course of moderate-to-very severe chronic obstructive pulmonary disease: the UPLIFT trial. Expert Rev Respir Med. 2010;4(3):279-289. doi: 10.1586/ers.10.23. Review. PubMed PMID: 20524910.

The Understanding Potential Long-term Improvements in Function with Tiotropium (UPLIFT ®) trial was a global, 4-year, randomised, placebo-controlled clinical trial that evaluated the long-term impact of tiotropium bromide 18 μg via HandiHaler® on the primary endpoints of the rates of decline in pre- and post-bronchodilator FEV1.

Secondary endpoints included lung function, health-related quality of life, exacerbations, exacerbation-related hospitalisations, mortality, safety, and tolerability. The study was carried out in 5,992 patients with moderate-to-very-severe COPD. Patients were permitted to receive prescribed treatment with long-acting beta2-agonists and/or inhaled corticosteroids in addition to the study drug.

The results failed to show an effect of tiotropium on the primary endpoints, but they did show sustained improvements in lung function and health-related quality of life, a reduction in the risk of exacerbations and related hospitalisations. Treatment with tiotropium also reduced all-cause mortality in patients on treatment over the 4-year trial period and reduced lower respiratory and cardiovascular morbidity, including respiratory failure and myocardial infarction.

Tashkin DP, Celli BR, Decramer M, Lystig T, Liu D, Kesten S. Efficacy of tiotropium in COPD patients with FEV1 ≥60% participating in the UPLIFT trial. COPD. 2012;9(3):289-296. doi: 10.3109/15412555.2012.656211. Epub 2012 Mar 20. PubMed PMID: 22432932.

Using data from UPLIFT®, a further analysis of a sub-category of GOLD stage II patients with post-bronchodilator FEV1 ≥60% predicted is presented. Outcomes include pre- and post-bronchodilator spirometry, exacerbations, SGRQ and mortality. It was shown that treatment with tiotropium 18 μg via HandiHaler® provides clinical efficacy in patients with GOLD stage II disease with an FEV1 ≥60% predicted, supporting current GOLD guidelines for COPD treatment.

Halpin DM, Decramer M, Celli B, Kesten S, Liu D, Tashkin DP. Exacerbation frequency and course of COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:653-661. doi: 10.2147/COPD.S34186. Epub 2012 Sep 21. PubMed PMID: 23055714; PubMed Central PMCID: PMC3459660.

Using a retrospective analysis of data from UPLIFT®, the association between frequency of exacerbation and spirometric and health status changes over time was examined. It was shown that increased exacerbation frequency worsens the rate of decline in lung function and health-related quality of life in patients with COPD. Increased rates of hospitalised exacerbations are associated with increased risk of death.

Tashkin D, Celli B, Kesten S, Lystig T, Decramer M. Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial. Respir Med. 2010;104(10):1495-1504. doi: 10.1016/j.rmed.2010.03.033. Epub 2010 Apr 24. PubMed PMID: 20418083.

Subgroup analyses using data from the UPLIFT® trial demonstrates that both men and women similarly benefit from treatment with tiotropium 18 μg via HandiHaler® with respect to lung function improvement, exacerbations and health status.

Troosters T, Celli B, Lystig T, et al; Uplift Investigators. Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial. Eur Respir J. 2010;36(1):65-73. doi: 10.1183/09031936.00127809. Epub 2010 Feb 25. PubMed PMID: 20185426.

Using data from the UPLIFT® trial, treatment with tiotropium 18 μg via HandiHaler® was compared with placebo in patients who were not using any maintenance medications at randomisation. Benefits were noted in the tiotropium treatment group with respect to the rate of decline in both lung function (LF) and QoL. Tiotropium treatment for COPD patients not on maintenance therapy is associated with benefits in disease progression.

UPLIFT® Subanalysis

Celli BR, Decramer M, Asijee GM, Kupas K, Taskin DP. Effects of tiotropium on exacerbations in patients with COPD with low or high risk of exacerbations: a post-hoc analysis from the 4-year UPLIFT® trial. J COPD F. 2015;2(2):122-130. doi: http://dx.doi.org/10.15326/jcopdf.2.2.2014.0155.

A post-hoc analysis of the UPLIFT® trial–4-year, randomized, double-blind, placebo-controlled, parallel-group trial of tiotropium HandiHaler® 18 μg or placebo once daily, of patients with moderate-to-very-severe COPD. Patients were allowed to use concurrent respiratory therapy with the exception of other inhaled anticholinergics. Co-primary endpoints were annual rate of decline in the mean FEV1 measured before and after bronchodilation. Secondary endpoints included exacerbations of COPD and related hospitalisations, and the rate of death from any cause and from lower respiratory conditions.

Inclusion criteria: Age ≥40 years old, smoking history ≥10 pack years, and diagnosis of COPD (post-bronchodilator FEV1 ≤70% predicted and FEV1/forced vital capacity ≤70%).

Exacerbations were defined as increases, or new onset of, more than 1 respiratory symptom with at least 1 symptom lasting for 3 or more days and requiring treatment with antibiotics and/or systemic corticosteroids.

SPIRIVA® Respimat® vs placebo

Bateman ED, Tashkin D, Siafakas N, et al. A one-year trial of tiotropium Respimat® plus usual therapy in COPD patients. Respir Med. 2010;104(10):1460-1472. doi: 10.1016/j.rmed.2010.06.004. PubMed PMID: 20620037.

In this randomised, double-blind study, patients received either tiotropium 5 µg daily or placebo via Respimat® Soft Mist Inhaler. Primary endpoints were trough FEV1 and time to first exacerbation. Lung function, exacerbations and quality of life were improved by tiotropium Respimat® treatment but a numerical imbalance was seen in all-cause mortality.

Bateman E, Singh D, Smith D, et al. Efficacy and safety of tiotropium Respimat® SMI in COPD in two 1-year randomised studies. Int J Chron Obstruct Pulmon Dis. 2010;5:197-208. PubMed PMID: 20714373; PubMed Central PMCID: PMC2921687.

Two 1-year studies evaluated the long-term efficacy and safety of tiotropium 5 or 10 µg daily versus placebo, inhaled via the Respimat® Soft Mist Inhaler. Four primary endpoints, trough FEV1, Mahler Transition Dyspnoea Index, SGRQ score, and exacerbations per patient year were examined. The Tiotropium Respimat® Soft Mist Inhaler 5 µg treatment arm demonstrated sustained improvements for patients with COPD relative to placebo and similar to the 10 µg dose but with a lower frequency of anticholinergic adverse events.

SPIRIVA® Respimat® vs ipratropium MDI vs placebo

Voshaar T, Lapidus R, Maleki-Yazdi R, et al. A randomised study of tiotropium Respimat® Soft Mist inhaler vs. ipratropium pMDI in COPD. Respir Med. 2008;102(1):32-41. Epub 2007 Nov 8. PubMed PMID: 17996436.

Two identical, 12-week, multi-national, randomised, double-blind, double-dummy, parallel-group, active- and placebo-controlled studies tested treatment with either inhaled tiotropium (5 or 10 µg) via Respimat® Soft Mist Inhaler once daily, ipratropium (36 µg) pMDI 4 times daily or placebo in COPD patients. It was shown that both tiotropium doses delivered via Respimat® Soft Mist Inhaler significantly improved lung function compared with ipratropium pMDI and placebo.

Respimat® Soft Mist Inhaler: The device

Brand P, Hederer B, Austen G, Dewberry H, Meyer T. Higher lung deposition with Respimat® Soft Mist inhaler than HFA-MDI in COPD patients with poor technique. Int J Chron Obstruct Pulmon Dis. 2008;3(4):763-770. PubMed PMID: 19281091; PubMed Central PMCID: PMC2650591.

Results from a 4-way, cross-over study detailing pulmonary deposition of drug in patients using poor technique both before and after training on the use of devices. It was found that drug deposition was greater in patients using the Respimat® Soft Mist Inhaler versus pressurised metered-dose inhalers.

Hodder R, Price D. Patient preferences for inhaler devices in chronic obstructive pulmonary disease: experience with Respimat® Soft Mist Inhaler. Int J Chron Obstruct Pulmon Dis. 2009;4:381-390. Epub 2009 Oct 19. Review. PubMed PMID: 19888356; PubMed Central PMCID: PMC2829861.

A report on patient preference of devices used for inhalation of medication in treatment of COPD. Respimat® Soft Mist Inhaler was found to be preferred over pressurised metered-dose inhalers and dry-powder inhalers.

Ferguson GT, Ghafouri M, Dai L, Dunn LJ. COPD patient satisfaction with ipratropium bromide/albuterol delivered via Respimat®: a randomized, controlled study. Int J Chron Obstruct Pulmon Dis. 2013;8:139-150. doi: 10.2147/COPD.S38577. Epub 2013 Mar 19. PubMed PMID: 23658479; PubMed Central PMCID: PMC3607534.

Patient satisfaction was recorded for the use of either metered-dose inhaler or Respimat® Soft Mist Inhaler to deliver ipratropium/albuterol. It was found that while efficacy and safety was similar between groups, patients preferred using the Respimat® Soft Mist Inhaler.

Recent ADIS Reviews

Lyseng-Williamson KA, Keating GM. Tiotropium Respimat® Soft Mist inhaler: a guide to its use in chronic obstructive pulmonary disease (COPD) in the EU. Drugs Ther Perspect. 2015;31(2):39-44.

An ADIS Drug Evaluation of SPIRIVA® Respimat® use in COPD. This independent review found that SPIRIVA® Respimat® improved lung function, reduced the number of COPD exacerbations requiring hospitalisation, improved HR-QOL, and reduced dyspnoea in patients with COPD. SPIRIVA® Respimat® is generally well tolerated, and the dose of SPIRIVA® delivered via Respimat® Soft Mist inhaler and the prolonged duration of the aerosol cloud should make it easier for patients to use.

Keating GM. Tiotropium Respimat® Soft Mist inhaler: a review of its use in chronic obstructive pulmonary disease. Drugs. 2014;74(15):1801-1816.

An ADIS Drug Evaluation of SPIRIVA® Respimat® use in COPD. In addition to what is reported in Lyseng-Williamson KA et al, this independent and comprehensive review includes results from the TIOSPIR® trial. Specifically, SPIRIVA® Respimat® was not inferior to SPIRIVA® HandiHaler® in all-cause mortality and the risk of cardiovascular mortality and major adverse cardiovascular events did not significantly differ between these regimens.