Real-world study of STIOLTO RESPIMAT vs LABA/ICS
26% lower risk of pneumonia vs LABA/ICS1
24% lower risk of exacerbation vs LABA/ ICS1
78% lower risk of escalation therapy vs LABA/ ICS1
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Results from real-world studies are not intended for comparisons with clinical trials. Real-world studies were observational trials. Differences in study designs, patient populations, outcome definitions, and methods of collecting data make it difficult to make comparisons with clinical trials or with each other. Real-world data should be viewed as complementary information.
LABA, long-acting beta2-agonist; ICS, inhaled corticosteroid; AHR, adjusted hazard ratio; CI, confidence interval.
Study Design & Limitations
Expand allA non-interventional analysis was completed comparing patients initiating STIOLTO RESPIMAT (tiotropium bromide and olodaterol) with patients on any LABA/ICS fixed-dose combination (FDC) in a US-based real-world setting.1
This study used administrative claims data from January 2013 through March 2019 in the HealthCore Integrated Research Database to examine the risk of COPD exacerbation.
After meeting all study criteria, there were 2684 patients on STIOLTO RESPIMAT and 59,301 patients on LABA/ICS remaining in the study cohort.
Key inclusion criteria were ≥1 prescription for STIOLTO RESPIMAT or LABA/ICS FDC between January 2013 through March 2019 (1st fill date=index date); ≥1diagnosis code indicating COPD in any position at any time prior to the index date; ≥1 year of continuous health plan eligibility prior to the index date; and aged ≥40 years at the index date.
Patients were excluded if they were aged <40 years at the index date; diagnosis of asthma in the year prior to the index date, lung cancer, interstitial lung disease, or lung transplant; or pre-index date use of STIOLTO RESPIMAT, LABA/ICS, or LABA/LAMA/ICS in free or fixed form.
After reweighting for stratified propensity scores, the total pseudo-population consisted of 2600 patients on STIOLTO RESPIMAT and 40,353 patients on LABA/ICS.
After reweighting, cohorts were well balanced on baseline characteristics. There was still some imbalance in prior exacerbation history, leading to severe exacerbations being adjusted for this model. Patients were followed until the earliest of the following: first occurrence of a COPD exacerbation, community-acquired pneumonia, escalation to triple therapy, switch in treatment, discontinuation of COPD treatment, the end of the study period, the end of continuous health plan eligibility, or (for the main analyses) 1 year after cohort entry.
The outcomes assessed included the risk of first COPD exacerbation as the primary outcome, with secondary outcomes including risk of hospitalization for community-acquired pneumonia, risk of escalation to triple therapy, and combined risk of these 3 outcomes.
LABA, long-acting beta2-agonist; ICS, inhaled corticosteroid; LAMA, long-acting muscarinic antagonist.
Fine stratification and reweighting by exposure propensity score was used to control for any confounding by treatment group; however, this was only possible for measured covariates, and therefore an impact of residual confounding by unmeasured confounders—such as lifestyle factors that are less critical to insurance billing—cannot be ruled out. Furthermore, the nature of the ICD diagnostic codes made it impossible to verify pneumonia as the primary driver of hospitalization. As with any observational study, prescriptions dispensed by a pharmacy but not taken by patients could lead to misclassification of exposure.
ICD, International Classification of Diseases.
Real-World evidence for switching from LABA/ICS to STIOLTO RESPIMAT vs triple therapy2
3.45 pt CAT improvement | 3.45 pt CAT improvement In the propensity score-matched set, patients who switched to RESPIMAT achieved a mean CAT score improvement of -3.45 points vs -2.51 points with LAMA/LABA/ICS at ~12 weeks. (Tio/Olo: 95% CI: −2.45, −4.45; TT: 95% CI: −1.62, −3.40) |
68% CAT responders | 68% CAT responders 67.9% of patients on STIOLTO RESPIMAT achieved a clinically meaningful CAT response (Δ ≥2 points) vs 56.3% on LAMA/LABA/ICS in the matched set. In the safety set: 70.6% (Tio/Olo) vs 57.4% (TT) |
65% good/excellent | 65% good/excellent The percentage of STIOLTO RESPIMAT patients rated as being in good/ excellent general condition (PGE score) increased from 42.9% at baseline to 65.2% at ~12 weeks, vs 33.9% to 53.8% with TT. |
Results from real-world studies are not intended for comparisons with clinical trials. Real-world studies were observational trials. Differences in study designs, patient populations, outcome definitions, and methods of collecting data make it difficult to make comparisons with clinical trials or with each other. Real-world data should be viewed as complementary information.
Study Design & Limitations
Expand allEVELUT (NCT03954132) was an open-label, real-world, observational, multicenter study of approximately 12 weeks’ duration conducted across 49 sites in Germany between June 2019 and June 2021.
The study compared fixed-dose LAMA/LABA (STIOLTO RESPIMAT [tiotropium/olodaterol]) vs any triple therapy (LAMA/LABA/ICS; fixed or free combination) in patients with symptomatic COPD at low exacerbation risk who were switched from LABA/ICS at their physician’s discretion.
The safety set comprised 463 patients (STIOLTO RESPIMAT, n=329; TT, n=134). Following propensity score matching on age, sex, mMRC score, CAT score, pack-years of smoking, and physician specialty, the matched set included 242 patients (Tio/Olo, n=121; TT, n=121). Of these, 111 patients in the Tio/Olo group and 118 patients in the TT group completed the mMRC and CAT questionnaires used for the primary endpoint analysis. Creation of a larger matched set retaining a standardized difference ≤0.1 in matched variables was not possible.
After matching, the two treatment groups were well balanced on key variables but showed some residual differences in duration of COPD, GOLD spirometry status, and prior respiratory therapies other than LABA/ICS. The majority of participants had moderate COPD (FEV1 50–79%; Tio/Olo 58.7%; TT 52.1%).
Key inclusion criteria were: age ≥40 years; physician-confirmed COPD diagnosis; symptomatic on LABA/ICS (mMRC ≥1 and CAT ≥10); and low exacerbation risk (<2 moderate exacerbations and no hospitalizations within the previous 12 months). Patients with a history of asthma, asthma–COPD overlap, or frequent/severe exacerbations were excluded.
Co-primary endpoints were changes in mMRC and CAT scores between baseline (Visit 1) and end of observation (~12 weeks; Visit 2). Secondary endpoints included Physician’s Global Evaluation (PGE) score, proportion of mMRC and CAT responders (Δ mMRC score ≥1; Δ CAT score ≥2), and patient satisfaction with the inhaler and therapy according to a seven-point ordinal scale.
Analysis of primary endpoints was based on propensity score matching, with sensitivity analyses performed using propensity score weighting and multivariable regression modelling. Based on the resulting sample size, it was possible to assess non-inferiority between Tio/Olo and TT in terms of mMRC score, but not for CAT score.
Despite propensity score matching, residual imbalances in spirometry status, exacerbation rates, and COPD duration suggest that TT patients may have had marginally more severe disease, and a higher drop-out rate in the STIOLTO RESPIMAT arm (7.9% vs 3.7%) introduces potential survivor bias—both of which may have led to overestimation of treatment effects in the STIOLTO RESPIMAT arm. Blood eosinophil counts were available for fewer than 10% of patients, precluding matching on eosinophil levels, FEV1, or exacerbation history. Treatment adherence was not verified by patient diary. The patient population was smaller than planned due to the COVID-19 pandemic (463 enrolled vs ~900 planned), and potential differences in outcomes between fixed-dose and free TT were not explored.
STIOLTO® RESPIMAT® (tiotropium bromide and olodaterol) Inhalation Spray is a combination of tiotropium, an anticholinergic, and olodaterol, a long-acting beta2-adrenergic agonist (LABA), indicated for the long-term, once-daily maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
Important Limitations of Use
STIOLTO is NOT indicated to treat acute deterioration of COPD and is not indicated to treat asthma.
CONTRAINDICATION
Use of a LABA, including STIOLTO RESPIMAT, without an inhaled corticosteroid (ICS) is contraindicated in patients with asthma.
STIOLTO is contraindicated in patients with hypersensitivity to tiotropium, ipratropium (atropine derivatives), olodaterol, or any component of this product.
In clinical trials and postmarketing experience with tiotropium, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported. Hypersensitivity reactions were also reported in clinical trials with STIOLTO.
WARNINGS AND PRECAUTIONS
LABA as monotherapy (without an ICS), for asthma increases the risk of asthma-related death, and in pediatric and adolescent patients, increases the risk of asthma-related hospitalizations.
Do not initiate STIOLTO in patients with acutely deteriorating COPD, which may be a life-threatening condition, or used as rescue therapy for acute symptoms. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.
STIOLTO should not be used more often or at higher doses than recommended, or with other LABAs as an overdose may result.
If immediate hypersensitivity reactions occur, such as urticaria, angioedema, rash, bronchospasm, anaphylaxis, or itching, discontinue STIOLTO at once and consider alternative treatment. Patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to STIOLTO.
If paradoxical bronchospasm occurs, discontinue STIOLTO immediately and institute alternative therapy.
STIOLTO can produce a clinically significant cardiovascular effect in some patients, as measured by increases in pulse rate, systolic or diastolic blood pressure, and/ or symptoms. If such effects occur, STIOLTO may need to be discontinued.
Use caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, in patients with known or suspected prolongation of the QT interval, and in patients who are unusually responsive to sympathomimetic amines.
Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a physician immediately if signs or symptoms of acute narrow-angle glaucoma develop.
Use with caution in patients with urinary retention especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
Patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) should be monitored closely for anticholinergic side effects.
Be alert to hypokalemia and hyperglycemia.
ADVERSE REACTIONS
The most common adverse reactions with STIOLTO (>3% incidence and higher than an active control) were: nasopharyngitis, 12.4% (11.7%/12.6%), cough, 3.9% (4.4%/3.0%), and back pain, 3.6% (1.8%/3.4%).
DRUG INTERACTIONS
Use caution if administering adrenergic drugs because sympathetic effects of olodaterol may be potentiated.
Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of olodaterol.
Use with caution in patients taking non–potassium-sparing diuretics, as the ECG changes and/or hypokalemia may worsen with concomitant beta-agonists.
The action of adrenergic agents on the cardiovascular system may be potentiated by monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval. Therefore, STIOLTO should be used with extreme caution in patients being treated with these drugs. Use beta-blockers with caution as they not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in patients with COPD.
Avoid co-administration of STIOLTO with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.
STIOLTO is for oral inhalation only.
The STIOLTO cartridge is only intended for use with the STIOLTO RESPIMAT inhaler.
Inform patients not to spray STIOLTO into the eyes as this may cause blurring of vision and pupil dilation.
CL-STO-100048 6.5.2019
Please see full Prescribing Information, Patient Information, and Instructions for Use for STIOLTO RESPIMAT.
References
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Quint JK, Montonen J, Esposito DB, et al. Effectiveness and safety of COPD maintenance therapy with tiotropium/olodaterol versus LABA/ICS in a US claims database. Adv Ther. 2021;38(5):2249-2270.
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Buhl R, Dreher M, Mattiucci-Guehlke M, et al. EVELUT®: a real-world, observational study assessing dyspnoea and symptom burden in COPD patients switched from LABA/ICS to LAMA/LABA or LAMA/LABA/ICS. Adv Ther. 2023;40(7):3263-3278.