Publications by authors named "Alberto de la Hoz"

17 Publications

  • Page 1 of 1

Effects of Tiotropium/Olodaterol on Activity-Related Breathlessness, Exercise Endurance and Physical Activity in Patients with COPD: Narrative Review with Meta-/Pooled Analyses.

Adv Ther 2021 02 11;38(2):835-853. Epub 2020 Dec 11.

Kingston General Hospital, Kingston, ON, Canada.

One of the most debilitating symptoms of chronic obstructive pulmonary disease (COPD) is breathlessness, which leads to avoidance of physical activities in daily living and hastens clinical deterioration. Treatment of patients with COPD with inhaled long-acting muscarinic antagonist (LAMA)/long-acting β-agonist (LABA) combination therapy improves airflow limitation, reduces breathlessness compared with LAMA or LABA monotherapies, and improves health status and quality of life. A large clinical trial programme focusing on the effects of tiotropium/olodaterol combination therapy demonstrated that this LAMA/LABA combination improves lung function and reduces hyperinflation (assessed by serial inspiratory capacity measurements) compared with either tiotropium alone or placebo in patients with COPD. Tiotropium/olodaterol also increases exercise endurance capacity and improves patient perception of the intensity of breathlessness compared with placebo. In this narrative review, we focus on the relationship between improving symptoms during activity, the ability to remain active in daily life and how this may impact quality of life. We consider the benefits of therapy optimisation by means of dual bronchodilation with tiotropium/olodaterol, and present new data from meta-analyses/pooled analyses showing that tiotropium/olodaterol improves inspiratory capacity compared with placebo and tiotropium and improves exercise endurance time compared with placebo after 6 weeks of treatment. We also discuss the importance of taking a holistic approach to improving physical activity, including pulmonary rehabilitation and exercise programmes in parallel with bronchodilator therapy and psychological programmes to support behaviour change.
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http://dx.doi.org/10.1007/s12325-020-01557-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889690PMC
February 2021

The effect of tiotropium/olodaterol versus fluticasone propionate/salmeterol on left ventricular filling and lung hyperinflation in patients with COPD.

BMJ Open Respir Res 2020 12;7(1)

Pulmonary Research Institute, LungenClinic Grosshansdorf GmbH, Airway Research Centre North (ARCN), Grosshansdorf, Germany.

This exploratory, randomised, double-blind, double-dummy, multicentre, cross-over study explored the effect of 6 weeks of treatment with tiotropium/olodaterol (T/O) versus fluticasone propionate/salmeterol (F/S) on left ventricular filling in patients with chronic obstructive pulmonary disease with functional residual capacity (FRC) >120% predicted and postbronchodilator improvement of FRC ≥7.5%. Overall, 76 patients were randomised across nine sites. Treatment with T/O or F/S increased left ventricular end-diastolic volume index from baseline (adjusted mean change: T/O: 2.317 mL/m, F/S: 2.855 mL/m), with no statistically significant difference between treatments. However, T/O resulted in a significantly greater reduction in lung hyperinflation versus F/S (FRC plethysmography absolute change from baseline: F/S: -0.329 L, T/O: -0.581 L).
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http://dx.doi.org/10.1136/bmjresp-2020-000741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713210PMC
December 2020

Tiotropium/Olodaterol Delays Clinically Important Deterioration Compared with Tiotropium Monotherapy in Patients with Early COPD: a Post Hoc Analysis of the TONADO Trials.

Adv Ther 2021 01 11;38(1):579-593. Epub 2020 Nov 11.

Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UK.

Introduction: Since chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, a composite endpoint of clinically important deterioration (CID) may provide a more holistic assessment of treatment efficacy. We compared long-acting muscarinic antagonist/long-acting β-agonist combination therapy with tiotropium/olodaterol versus tiotropium alone using a composite endpoint for CID. CID was evaluated overall and in patients with low exacerbation history (at most one moderate exacerbation in the past year [not leading to hospitalisation]), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 patients and maintenance-naïve patients with COPD. We assessed whether early treatment optimisation is more effective with tiotropium/olodaterol versus tiotropium in delaying and reducing the risk of CID.

Methods: Data were analysed from 2055 patients treated with either tiotropium/olodaterol 5/5 μg or tiotropium 5 μg (delivered via Respimat) in two replicate, 52-week, parallel-group, double-blind studies (TONADO 1/2). CID was defined as a decline of at least 0.1 L from baseline in trough forced expiratory volume in 1 s, increase from baseline of at least 4 units in St. George's Respiratory Questionnaire score, or moderate/severe exacerbation. Time to first occurrence of one of these events was recorded as time to first CID.

Results: Overall, treatment with tiotropium/olodaterol significantly increased the time to, and reduced the risk of, CID versus tiotropium (median time to CID 226 versus 169 days; hazard ratio [HR] 0.76 [95% confidence interval 0.68, 0.85]; P < 0.0001). Significant reductions were also observed in patients with low exacerbation history (241 versus 170; HR 0.73 [0.64, 0.83]; P < 0.0001), GOLD 2 patients (241 versus 169; 0.72 [0.61, 0.84]; P < 0.0001) and maintenance-naïve patients (233 versus 171; 0.75 [0.62, 0.91]; P = 0.0030).

Conclusion: In patients with COPD, including patients with low exacerbation history, GOLD 2 patients and maintenance-naïve patients, tiotropium/olodaterol reduced the risk of CID versus tiotropium. These results demonstrate the advantages of treatment optimisation with tiotropium/olodaterol over tiotropium monotherapy.

Trial Registration: ClinicalTrials.gov identifier: TONADO 1 and 2 (NCT01431274 and NCT01431287, registered 8 September 2011).
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http://dx.doi.org/10.1007/s12325-020-01528-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854451PMC
January 2021

Blood eosinophils as a biomarker of future COPD exacerbation risk: pooled data from 11 clinical trials.

Respir Res 2020 Sep 17;21(1):240. Epub 2020 Sep 17.

Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

Background: Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation and chronic inflammation. Predicting exacerbations of COPD, which contribute to disease progression, is important to guide preventative treatment and improve outcomes. Blood eosinophils are a biomarker for patient responsiveness to inhaled corticosteroids (ICS); however, their effectiveness as a predictive biomarker for COPD exacerbations is unclear.

Methods: This post hoc analysis pooled data from 11 Boehringer Ingelheim-sponsored Phase III and IV randomised COPD studies with similar methodologies. Exacerbation data were collected from these studies, excluding patients from the ICS withdrawal arm of the WISDOM® study. Patients were grouped according to their baseline blood eosinophil count, baseline ICS use and number of exacerbations in the year prior to each study.

Results: Exacerbation rate data and baseline eosinophil count were available for 22,125 patients; 45.6% presented with a baseline blood eosinophil count of ≤ 150 cells/μL, 34.3% with 150-300 cells/μL and 20.1% with > 300 cells/μL. The lowest exacerbation rates were observed in patients with ≤ 150 cells/μL, with small increases in exacerbation rate observed with increasing eosinophil count. When stratified by exacerbation history, the annual rate of exacerbations for patients with 0 exacerbations in the previous year increased in line with increasing eosinophil counts (0.38 for ≤ 150 cells/μL, 0.39 for 150-300 cells/μL and 0.44 for > 300 cells/μL respectively). A similar trend was identified for patients with one exacerbation in the previous year, 0.62, 0.66 and 0.67 respectively. For patients with ≥ 2 exacerbations, exacerbation rates fluctuated between 1.02 (≤ 150 cells/μL) to 1.10 (150-300 cells/μL) and 1.07 (> 300 cells/μL). Higher exacerbation rates were noted in patients treated with ICS at baseline (range 0.75 to 0.82 with increasing eosinophil count) compared with patients not on ICS (range 0.45 to 0.49).

Conclusion: We found no clinically important relationship between baseline blood eosinophil count and exacerbation rate. Hence, the current analysis does not support the use of blood eosinophils to predict exacerbation risk; however, previous exacerbation history was found to be a more reliable predictor of future exacerbations.

Trial Registration: ClinicalTrials.gov Identifiers: NCT00168844 , NCT00168831 , NCT00387088 , NCT00782210 , NCT00782509 , NCT00793624 , NCT00796653 , NCT01431274 , NCT01431287 , NCT02296138 and NCT00975195 .
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http://dx.doi.org/10.1186/s12931-020-01482-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499955PMC
September 2020

COPD Maintenance Therapy with Tiotropium/Olodaterol Compared with Tiotropium: An Analysis in the Absence of Additional ICS Therapy.

COPD 2020 Oct 15;17(5):477-484. Epub 2020 Sep 15.

Pneumology Department, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.

The American Thoracic Society guidelines recommend long-acting β-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilation over LAMA or LABA monotherapy as maintenance therapy for patients with chronic obstructive pulmonary disease suffering from dyspnea or exercise intolerance. Previous studies, which included patients receiving background inhaled corticosteroids (ICS), have shown the benefits of dual bronchodilation over monotherapy. This analysis aimed to confirm the benefits of LAMA/LABA over LAMA alone, without any confounding effects from ICS use. This pooled analysis compared the efficacy of tiotropium/olodaterol with tiotropium alone in patients from the TONADO and OTEMTO clinical trials who were not receiving ICS at study entry or during the studies. We analyzed change from baseline in trough forced expiratory volume in 1 s (FEV), St. George's Respiratory Questionnaire (SGRQ) score and Transition Dyspnea Index (TDI) score in all patients, by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage, baseline SGRQ score, and Baseline Dyspnea Index score. In this analysis of 1596 patients, tiotropium/olodaterol improved trough FEV, SGRQ and TDI compared with tiotropium alone. The observed mean differences were: trough FEV, 0.054 L (95% confidence interval [CI] 0.036, 0.073;  < 0.001); SGRQ, -1.918 (95% CI -2.994, -0.843;  < 0.001); and TDI, 0.575 (95% CI 0.301, 0.848;  < 0.001). Similar improvements were seen in each of the subgroup analyses. Tiotropium/olodaterol therapy significantly improved lung function, symptoms and health status compared with tiotropium alone. In a population free from ICS treatment, these data confirm the benefits of dual bronchodilation versus monotherapy.
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http://dx.doi.org/10.1080/15412555.2020.1813269DOI Listing
October 2020

A Post Hoc Holter ECG Analysis of Olodaterol and Formoterol in Moderate-to-Very-Severe COPD.

Int J Chron Obstruct Pulmon Dis 2020 10;15:1955-1965. Epub 2020 Aug 10.

Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany, Member of the German Center for Lung Research (DZL).

Background: Patients with chronic obstructive pulmonary disease (COPD) are at risk of developing cardiac arrhythmias and elevated heart rate. A theoretical mechanistic association based on the interaction of long-acting β-agonists (LABAs) with adrenoreceptors in the heart and vasculature is assumed as a potential class-related risk. Therefore, we performed a pooled analysis of Holter electrocardiogram (ECG) data from four 48-week, randomized, double-blind, placebo-controlled, parallel-group, Phase III clinical trials evaluating olodaterol (5 μg or 10 μg) or formoterol (12 µg) versus placebo.

Methods: We analyzed Holter ECG data from a representative subset of 775 patients with Global Initiative for Chronic Obstructive Lung Disease stage 2-4 COPD from four studies (1222.11-14) assessing olodaterol (5 μg and 10 μg) and formoterol (12 µg) versus placebo.

Results: No statistically significant (P>0.3) or clinically relevant differences in the shift from baseline of premature supraventricular or ventricular beats were observed among the active treatment and the placebo groups. Minor and transient differences were observed in the adjusted mean heart rate from baseline during treatment in all groups. There was a numerically small but statistically significant increase for formoterol at Week 24, olodaterol 5 μg at Weeks 12 and 40, and olodaterol 10 μg at Week 40 (all less than 3.0 beats per minute). Mean heart rates returned to a statistically non-significant change at Week 48 for all treatment groups. No increase in major adverse cardiovascular events was observed.

Conclusion: Treatment with olodaterol or formoterol is not associated with arrhythmias or a persistent increase in heart rate as assessed by Holter ECG in patients with COPD.

Trial Registration: ClinicalTrials.gov identifiers: NCT00782210 (1222.11); NCT00782509 (1222.12); NCT00793624 (1222.13); NCT00796653 (1222.14).
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http://dx.doi.org/10.2147/COPD.S246353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428408PMC
August 2020

No Influence on Cardiac Arrhythmia or Heart Rate from Long-Term Treatment with Tiotropium/Olodaterol versus Monocomponents by Holter ECG Analysis in Patients with Moderate-to-Very-Severe COPD.

Int J Chron Obstruct Pulmon Dis 2020 10;15:1945-1953. Epub 2020 Aug 10.

Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany, Member of the German Center for Lung Research (DZL).

Background: Patients with chronic obstructive pulmonary disease (COPD) and cardiovascular comorbidities may have an increased risk of medication-related cardiac arrhythmias. We therefore performed an analysis of Holter electrocardiogram (ECG) data from two large, long-term, controlled clinical COPD trials to investigate whether tiotropium/olodaterol increased the risk of cardiac arrhythmia and mean heart rate.

Methods: We analyzed Holter ECG data from a representative subset of patients (N=506) from the two pooled replicate studies (TONADO 1 and 2) assessing tiotropium/olodaterol 5/5 µg therapy versus tiotropium 5 µg or olodaterol 5 µg monotherapy, inhaled once daily (two single inhalations) using the Respimat Soft Mist™ inhaler device. Additionally, major adverse cardiac events (MACE) with tiotropium/olodaterol were assessed versus the respective monotherapies.

Results: After 12 weeks of treatment, there was no difference in the number of patients who had an increase or decrease from baseline in 24-hour supraventricular premature beats or ventricular premature beats between tiotropium/olodaterol 5/5 µg combination therapy and its monocomponents. Compared with baseline, a small but statistically significant increase in adjusted mean heart rate was observed for tiotropium 5 µg (+1.6 beats per minute [bpm]; P=0.0010), but no difference was observed for olodaterol 5 µg (+0.3 bpm; P=0.2778) or tiotropium/olodaterol 5/5 µg (-0.1 bpm; P=0.4607). MACE and fatal MACE were limited to 1 to 3 patients across treatment groups.

Conclusion: Compared with the compounds given as monotherapy, treatment with tiotropium/olodaterol fixed-dose combination therapy is not associated with medically relevant or statistically significant effects on arrhythmia as assessed by Holter ECG. Based on these findings, there is no evidence to assume a clinically relevant impact on cardiac function from dual tiotropium/olodaterol treatment.

Trial Registration: TONADO 1 (ClinicalTrials.gov: NCT01431274); TONADO 2 (ClinicalTrials.gov: NCT01431287).
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http://dx.doi.org/10.2147/COPD.S246350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429402PMC
August 2020

Absence of Adverse Effects of Tiotropium/Olodaterol Compared with the Monocomponents on Long-Term Heart Rate and Blood Pressure in Patients with Moderate-to-Very-Severe COPD.

Int J Chron Obstruct Pulmon Dis 2020 10;15:1935-1944. Epub 2020 Aug 10.

Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany, Member of the German Center for Lung Research (DZL).

Introduction: Long-acting β-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are established maintenance bronchodilator treatments for chronic obstructive pulmonary disease (COPD) with the potential to increase heart rate (HR) and impact blood pressure (BP). While previous studies indicate that HR and BP are not negatively influenced by tiotropium or olodaterol monotherapy, the effect of tiotropium/olodaterol has not been evaluated. We report a post hoc analysis of the effect of dual bronchodilation with tiotropium/olodaterol versus monocomponents on HR and BP in patients with moderate-to-very-severe COPD included in the large TONADO study.

Methods: The TONADO trials (1237.5 [NCT01431274] and 1237.6 [NCT01431287]) were two replicate, randomized, double-blind, parallel-group, 52-week, Phase III trials that compared tiotropium/olodaterol (5/5 μg and 2.5/5 μg) with tiotropium (5 μg and 2.5 μg) and olodaterol (5 μg) in patients with moderate-to-very-severe COPD. Patients with cardiovascular comorbidities were included. Changes in HR and systolic/diastolic BP were measured before and after dosing with the study medication at each visit (baseline, Week 12, Week 24 and Week 52).

Results: Overall, 3,100 patients were included in this analysis. Over 52 weeks, small changes from baseline in mean HR (<2 beats per minute [bpm]) and small changes from pre- to post-dose (<1 bpm) were evident at different time points. There was a non-significant increase from baseline in mean diastolic and systolic BP (<2 mmHg) observed over 52 weeks of treatment. The short-term (1 hour pre- to 1 hour post-dose) mean changes in systolic and diastolic BP over 52 weeks in the tiotropium/olodaterol 5/5 µg group were comparable with those observed for the monocomponents at all time points.

Conclusion: There were no differences in HR or BP among patients on tiotropium/olodaterol when compared with monocomponents. This supports the already demonstrated cardiovascular safety profile of tiotropium/olodaterol as long-acting maintenance bronchodilator treatment for COPD, including patients with cardiovascular comorbidities.
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http://dx.doi.org/10.2147/COPD.S246348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428407PMC
August 2020

Tiotropium/Olodaterol Decreases Exacerbation Rates Compared with Tiotropium in a Range of Patients with COPD: Pooled Analysis of the TONADO/DYNAGITO Trials.

Adv Ther 2020 10 10;37(10):4266-4279. Epub 2020 Aug 10.

Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

Introduction: Previous studies demonstrated that tiotropium/olodaterol reduced rates of exacerbations in patients with chronic obstructive pulmonary disease (COPD). However, this should be examined in a wider population.

Methods: This post hoc analysis pooled data from TONADO 1 + 2 and DYNAGITO, three 52-week, parallel-group, randomised, double-blind, phase III trials investigating patients with moderate-to-very severe COPD, with and without previous exacerbations, who received tiotropium/olodaterol 5/5 µg or tiotropium 5 µg. Subgroup analyses were conducted on patients stratified by exacerbation history, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2-4 disease severity and baseline inhaled corticosteroid (ICS) use.

Results: In 9942 patients, tiotropium/olodaterol was associated with lower rates of moderate/severe exacerbations (0.68 vs. 0.77 per patient-year; rate ratio (RR) vs. tiotropium 0.89, 95% confidence interval (CI) 0.84, 0.95; P = 0.0003) and exacerbations requiring hospitalisation (0.11 vs. 0.13 per patient-year; RR 0.86, 95% CI 0.75, 0.99; P = 0.0380) versus tiotropium. Lower rates of moderate/severe exacerbations with tiotropium/olodaterol versus tiotropium were evident in patients with 0-1 moderate exacerbation in the previous year (0.54 vs. 0.60 per patient-year; RR 0.90, 95% CI 0.82, 0.98; P = 0.0187) and at least two moderate or at least one severe exacerbation(s) in the previous year (0.97 vs. 1.09 per patient-year; RR 0.89, 95% CI 0.82, 0.97; P = 0.0096). In patients with GOLD 2 and GOLD 3 COPD, moderate/severe exacerbation rates were lower with tiotropium/olodaterol versus tiotropium; GOLD 4 patients showed negligible difference between treatments. When evaluating patients by baseline ICS use, there was a significantly lower rate of moderate/severe exacerbations with tiotropium/olodaterol versus tiotropium in patients receiving ICS.

Conclusions: Tiotropium/olodaterol decreased the rate of moderate/severe exacerbations and exacerbations leading to hospitalisation versus tiotropium. Results from this large, pooled, post hoc analysis support the use of dual bronchodilation with tiotropium/olodaterol in a broad range of patients, reflective of patients with COPD in clinical practice.

Trial Registration: TONADO 1 (ClinicalTrials.gov: NCT01431274); TONADO 2 (ClinicalTrials.gov: NCT01431287); DYNAGITO (ClinicalTrials.gov: NCT02296138). People with chronic obstructive pulmonary disease (COPD) may have times when their symptoms worsen, known as exacerbations. This may mean that they need to take additional medications, such as antibiotics or oral steroids. Studies have shown that a combination of two types of inhaled medicine-tiotropium and olodaterol-can help to reduce exacerbations in some people. To see if this is also the case across a larger and more diverse range of people, we combined the results from three studies (TONADO 1 + 2 and DYNAGITO) that looked at people who were taking tiotropium and olodaterol together and people who were taking tiotropium alone. We showed that, across a wide range of people, treatment with tiotropium/olodaterol was generally better at reducing exacerbations than tiotropium. Tiotropium/olodaterol also decreased the number of exacerbations that led to hospitalisation compared with tiotropium. Overall, our results support the use of combined tiotropium/olodaterol in people at different stages of COPD.
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http://dx.doi.org/10.1007/s12325-020-01438-3DOI Listing
October 2020

Efficacy of Tiotropium/Olodaterol Compared with Tiotropium as a First-Line Maintenance Treatment in Patients with COPD Who Are Naïve to LAMA, LABA and ICS: Pooled Analysis of Four Clinical Trials.

Adv Ther 2020 10 15;37(10):4175-4189. Epub 2020 Jul 15.

Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA.

Introduction: The efficacy of tiotropium/olodaterol compared with tiotropium in patients with chronic obstructive pulmonary disease (COPD) has been demonstrated in a large clinical programme. Currently, randomised controlled trial (RCT) data on dual bronchodilation as first-line maintenance therapy are limited. In this post hoc analysis of pooled data from four RCTs, we compared the efficacy of tiotropium/olodaterol versus tiotropium as maintenance therapy in patients with COPD who were not receiving maintenance treatment with long-acting muscarinic antagonists (LAMAs), long-acting β-agonists (LABAs) or inhaled corticosteroids (ICS) ("maintenance naïve") at study entry.

Methods: TONADO 1/2 (52 weeks) and OTEMTO 1/2 (12 weeks) were phase III RCTs in patients with COPD. TONADO 1/2 and OTEMTO 1/2 enrolled patients with post-bronchodilator forced expiratory volume in 1 s (FEV) < 80% predicted (lower limit FEV ≥ 30% in OTEMTO 1/2 only). We examined the effect of tiotropium/olodaterol 5/5 µg versus tiotropium 5 µg on trough FEV response, St. George's Respiratory Questionnaire (SGRQ) total score and Transition Dyspnoea Index (TDI) focal score at 12 weeks in four pooled studies.

Results: The pooled analysis included 1078 maintenance-naïve patients. There were significant improvements with tiotropium/olodaterol versus tiotropium in trough FEV [0.056 L; 95% confidence interval (CI) 0.033, 0.079; P < 0.0001], SGRQ score (- 1.780; 95% CI - 3.126 to - 0.434; P = 0.0096) and TDI score (0.409; 95% CI 0.077, 0.741; P = 0.0158) at week 12. For patients receiving tiotropium/olodaterol, the odds of achieving a minimal clinically important difference from baseline in any of the analysed outcomes (FEV ≥ 0.1 L, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) were higher versus tiotropium.

Conclusions: In patients who were maintenance naïve at baseline, treatment initiation with tiotropium/olodaterol resulted in greater improvements in lung function, health status and dyspnoea severity compared with tiotropium alone, without compromising patient safety. These results support the use of dual bronchodilation with tiotropium/olodaterol as first-line maintenance treatment in patients with COPD.

Trial Registration: ClinicalTrials.gov: TONADO 1 and 2 (NCT01431274 and NCT01431287, registered 8 September 2011) and OTEMTO 1 and 2 (NCT01964352 and NCT02006732, registered 14 October 2013).
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http://dx.doi.org/10.1007/s12325-020-01411-0DOI Listing
October 2020

Benefits of Tiotropium/Olodaterol Compared with Tiotropium in Patients with COPD Receiving only LAMA at Baseline: Pooled Analysis of the TONADO and OTEMTO Studies.

Adv Ther 2020 08 27;37(8):3485-3499. Epub 2020 May 27.

Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA.

Introduction: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting β-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted.

Methods: TONADO 1&2 and OTEMTO 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with LAMA monotherapy at baseline who were randomised to receive either 5 µg tiotropium (LAMA) or 5/5 µg tiotropium/olodaterol (LAMA/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV), St. George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI).

Results: Overall, 151 patients received tiotropium; 148 received tiotropium/olodaterol. Mean differences from baseline with tiotropium/olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV, - 2.675 (95% CI - 5.060, - 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/olodaterol versus tiotropium for trough FEV (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P < 0.0001), SGRQ (OR 1.49, 95% CI 0.93, 2.40; P = 0.0980) and TDI (OR 2.81, 95% CI 1.71, 4.60; P < 0.0001). Minimum clinically important difference from baseline in any of the analysed outcomes (FEV ≥ 0.1 l, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) was more likely in patients treated with tiotropium/olodaterol versus tiotropium (OR 2.43, 95% CI 1.32, 4.51; P = 0.0046).

Conclusion: In patients with COPD receiving only LAMA monotherapy, treatment escalation to tiotropium/olodaterol resulted in statistically significant and clinically relevant improvements in lung function, health status and breathlessness. These results support early therapy optimisation to dual bronchodilation with tiotropium/olodaterol in patients receiving tiotropium alone.

Trial Registration: TONADO 1 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431274). TONADO 2 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431287). OTEMTO 1 was registered in the US National Library of Medicine on 17 October 2013 (Clinicaltrials.gov: NCT01964352). OTEMTO 2 was registered in the US National Library of Medicine on 10 December 2013 (Clinicaltrials.gov: NCT02006732).
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http://dx.doi.org/10.1007/s12325-020-01373-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370969PMC
August 2020

A comparison of tiotropium, long-acting β-agonists and leukotriene receptor antagonists on lung function and exacerbations in paediatric patients with asthma.

Respir Res 2020 Jan 13;21(1):19. Epub 2020 Jan 13.

Klinik für Kinder und Jugendmedizin, Evangelisches Klinikum Bethel, Bielefeld, and Allergy Center of the Ruhr University, Bochum, Germany.

Diagnosing and treating asthma in paediatric patients remains challenging, with many children and adolescents remaining uncontrolled despite treatment. Selecting the most appropriate pharmacological treatment to add onto inhaled corticosteroids (ICS) in children and adolescents with asthma who remain symptomatic despite ICS can be difficult. This literature review compares the efficacy and safety of long-acting β-agonists (LABAs), leukotriene receptor antagonists (LTRAs) and long-acting muscarinic antagonists (LAMAs) as add-on treatment to ICS in children and adolescents aged 4-17 years.A literature search identified a total of 29 studies that met the inclusion criteria, including 21 randomised controlled trials (RCTs) of LABAs versus placebo, two RCTs of LAMAs (tiotropium) versus placebo, and four RCTs of LTRA (montelukast), all as add-on to ICS. In these studies, tiotropium and LABAs provided greater improvements in lung function than LTRAs, when compared with placebo as add-on to ICS. Although exacerbation data were difficult to interpret, tiotropium reduced the risk of exacerbations requiring oral corticosteroids when added to ICS, with or without additional controllers. LABAs and LTRAs had a comparable risk of asthma exacerbations with placebo when added to ICS. When adverse events (AEs) or serious AEs were analysed, LABAs, montelukast and tiotropium had a comparable safety profile with placebo.In conclusion, this literature review provides an up-to-date overview of the efficacy and safety of LABAs, LTRAs and LAMAs as add-on to ICS in children and adolescents with asthma. Overall, tiotropium and LABAs have similar efficacy, and provide greater improvements in lung function than montelukast as add-on to ICS. All three controller options have comparable safety profiles.
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http://dx.doi.org/10.1186/s12931-020-1282-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958672PMC
January 2020

Efficacy of once-daily tiotropium Respimat in adults with asthma at GINA Steps 2-5.

Pulm Pharmacol Ther 2020 02 23;60:101881. Epub 2019 Dec 23.

Genomics and Precision Medicine, University of Arizona College of Medicine, Tucson, AZ, USA. Electronic address:

Tiotropium Respimat is an efficacious add-on to maintenance treatment in patients with symptomatic asthma. Currently, the Global Initiative for Asthma (GINA) strategy recommends tiotropium for patients at Steps 4-5. To assess the clinical benefits of tiotropium Respimat across asthma severities, GINA Steps 2-5, a post hoc analysis of five double-blind trials (12-48-weeks; patients aged 18-75 years) investigated the effect of tiotropium Respimat, 5 μg or 2.5 μg, versus placebo, on peak forced expiratory volume in 1 s (FEV) within 3 h post-dose (FEV) response, and Asthma Control Questionnaire-7 (ACQ-7) responder rate. GINA step grouping was based on patients' background treatment regimen. Baseline characteristics of patients (N = 2926) were balanced between treatments. Tiotropium Respimat showed consistent improvements in lung function across GINA steps; placebo-corrected peak FEV improvements after tiotropium Respimat 5 μg and 2.5 μg were: Step 2 (Week 8), 135 mL (95% confidence interval: 84, 187) and 155 mL (103, 206); Step 3 (Week 24), 187 mL (139, 235) and 235 mL (187, 283); Step 4 (Week 24), 111 mL (63, 159) and 181 mL (35, 326); Step 5 (Week 24; 5 μg only), 164 mL (5, 323). Asthma control improved with tiotropium Respimat versus placebo, showing statistical significance (nominal P value) with tiotropium Respimat 5 μg at Step 4 (odds ratio 1.36 [1.03, 1.78]). Safety profiles were similar between treatments. In conclusion, tiotropium Respimat add-on therapy improves lung function, and may improve asthma control, in adults across disease severities.
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http://dx.doi.org/10.1016/j.pupt.2019.101881DOI Listing
February 2020

Tiotropium Respimat® add-on therapy to inhaled corticosteroids in patients with symptomatic asthma improves clinical outcomes regardless of baseline characteristics.

Respir Med 2019 Oct - Nov;158:97-109. Epub 2019 Sep 30.

University of Groningen, University Medical Center Groningen, Department of Pulmonary Medicine and Tuberculosis and Groningen Research Institute for Asthma and COPD, Groningen, Netherlands.

Background: Despite currently available therapies and detailed treatment guidelines, many patients with asthma remain symptomatic. Tiotropium delivered by the soft mist inhaler Respimat®, as add-on therapy to medium-dose inhaled corticosteroids (ICS), has been shown to improve lung function and asthma control in patients with symptomatic moderate asthma.

Objective: To determine whether the efficacy of tiotropium Respimat® in asthma differs by patients' study baseline characteristics.

Methods: Two replicate Phase III, randomized, double-blind, placebo-controlled, parallel-group studies (MezzoTinA-asthma®; NCT01172808 and NCT01172821) of once-daily tiotropium Respimat 5 μg and 2.5 μg add-on to ICS were conducted in patients with symptomatic asthma despite treatment with medium-dose ICS with or without additional controllers. Subgroup analyses of peak forced expiratory volume in 1 s (FEV), trough FEV, risk of severe asthma exacerbation and Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by patients' baseline characteristics.

Results: In this analysis, 523 patients received placebo while 517 and 519 patients received the 5 μg and 2.5 μg dose of tiotropium Respimat, respectively. The magnitude of the improvements in lung function and asthma control, as well as the reduced risk of severe exacerbation with both doses of tiotropium Respimat versus placebo, was independent of a broad range of baseline characteristics.

Conclusions: Once-daily tiotropium Respimat as add-on to ICS is a beneficial treatment option for patients with asthma who remain symptomatic despite at least medium-dose ICS, regardless of baseline characteristics.
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http://dx.doi.org/10.1016/j.rmed.2019.09.014DOI Listing
August 2020

Commentary: Treating Pediatric Asthma According Guidelines.

Front Pediatr 2019 27;7:109. Epub 2019 Mar 27.

Klinik für Kinder- und Jugendmedizin, Evangelisches Klinikum Bethel, Bielefeld, Germany.

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http://dx.doi.org/10.3389/fped.2019.00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446829PMC
March 2019

Safety of tiotropium/olodaterol in chronic obstructive pulmonary disease: pooled analysis of three large, 52-week, randomized clinical trials.

Respir Med 2018 10 28;143:67-73. Epub 2018 Aug 28.

Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, 6 West Derby Street, Liverpool, L7 8TX, UK. Electronic address:

Background: An extensive clinical trial program supports the efficacy and safety of tiotropium/olodaterol in chronic obstructive pulmonary disease (COPD). We examined the safety of tiotropium/olodaterol compared with tiotropium in a large population of patients, focusing on cardiovascular and respiratory events.

Methods: Patients (n = 9942) who received once-daily tiotropium/olodaterol 5/5 μg or tiotropium 5 μg (via Respimat) in TONADO 1 & 2 and DYNAGITO were included. The number of patients and exposure-adjusted rate of events are presented for adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, and cardiovascular and respiratory events.

Findings: Fewer patients discontinued due to AEs with tiotropium/olodaterol (5.9%) versus tiotropium (7.9%; rate ratio [RR] 0.72; 95% confidence interval [CI] 0.62-0.84). There was no significant difference in the incidence of AEs, SAEs, cardiovascular AEs or central nervous system vascular AEs between treatments. Incidences of major adverse cardiovascular events (MACE) were 2.11 per 100 patient-years with tiotropium/olodaterol and 2.22 with tiotropium (RR 0.95; 95% CI 0.72-1.25), and incidences of fatal MACE (including death with undetermined cause) were 0.91 and 1.00 per 100 patient-years with tiotropium/olodaterol and tiotropium, respectively (RR 0.91; 95% CI 0.60-1.37). Respiratory AEs were generally balanced between treatment groups.

Conclusions: These results provide robust evidence that the benefits of tiotropium/olodaterol versus tiotropium are not at the expense of an increased risk of safety events. The combination is a suitable option for patients with COPD, even in the presence of cardiovascular risk factors.

Clinical Trials Registration: clinicaltrials. gov (TONADO 1 and 2: NCT01431274, NCT01431287; DYNAGITO: NCT02296138).
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http://dx.doi.org/10.1016/j.rmed.2018.08.012DOI Listing
October 2018

Tiotropium/olodaterol versus tiotropium in Japanese patients with COPD: results from the DYNAGITO study.

Int J Chron Obstruct Pulmon Dis 2018 13;13:2147-2156. Epub 2018 Jul 13.

Osaka Saiseikai Noe Hospital, Osaka, Japan.

Background: The DYNAGITO study was a Phase IIIb, randomized, double-blind, multicenter, active-controlled, parallel-group, 52-week study designed to determine the efficacy and safety of tiotropium and olodaterol combination therapy (TIO+OLO 5/5 μg) versus tiotropium monotherapy (TIO 5 μg) for reducing moderate-to-severe exacerbations of COPD. This is a prespecified analysis of the DYNAGITO data in Japanese patients.

Patients And Methods: Enrolled patients had a diagnosis of COPD with at least one moderate-to-severe exacerbation in the previous 12 months. Of the total 7,880 treated patients in the DYNAGITO study, 461 (TIO+OLO 5/5 μg: n=226, TIO 5 μg: n=235) were Japanese. The primary endpoint was the annualized rate of moderate-to-severe COPD exacerbations. The key secondary endpoint was the time to first moderate-to-severe COPD exacerbation, and other secondary endpoints included the annualized rate of exacerbations leading to hospitalization, time to first COPD exacerbation leading to hospitalization, and all-cause mortality. Safety data were analyzed descriptively.

Results: Combination therapy with TIO+OLO resulted in a 29% lower rate of moderate-to-severe COPD exacerbations relative to TIO monotherapy (rate ratio 0.71; 99% CI: 0.46, 1.10; =0.0434). The risk of a first moderate-to-severe COPD exacerbation was 19% lower with TIO+OLO combination therapy than with TIO monotherapy (HR 0.81; 99% CI: 0.57, 1.17; =0.1379), although this difference was not statistically significant. The annualized rate of COPD exacerbations requiring hospitalization was 14% lower in the TIO+OLO arm than in the TIO arm (rate ratio 0.86; 95% CI: 0.52, 1.42; =0.5654). The adverse event incidence was balanced between treatment arms.

Conclusion: In a prespecified subgroup analysis of Japanese patients in the DYNAGITO study, combination therapy with TIO+OLO was more effective than TIO in reducing exacerbations. Both treatments were well tolerated.
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http://dx.doi.org/10.2147/COPD.S169941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049061PMC
January 2019