Cardiovascular events and all-cause mortality in patients with chronic obstructive pulmonary disease using olodaterol and other long-acting beta2-agonists.

PURPOSE: We examined the effect of olodaterol on the risk of myocardial ischaemia, cardiac arrhythmia, and all-cause mortality compared with use of other long-acting beta2-agonists (LABAs). Channelling bias was also explored. METHODS: This Danish population-based cohort study used data linked from registries of hospital diagnoses, outpatient dispensings, and deaths. It included patients (aged ≥40 years) with a diagnosis of chronic obstructive pulmonary disease (COPD) who initiated olodaterol or another LABA. Using matching and propensity score (PS) stratification, we calculated adjusted incidence rate ratios (IRRs) using Poisson regression, followed by several additional analyses to evaluate and control channelling bias. RESULTS: The IRRs of cardiac arrhythmias or myocardial ischaemia among users of olodaterol (n = 14 239) compared to users of other LABAs (n = 51 167) ranged from 0.96 to 1.65 in various analyses, although some estimates had low precision. Initial analysis suggested an increased risk for death with olodaterol compared with other LABAs (IRR, 1.63; 95% CI, 1.44-1.84). Because olodaterol prescribing was associated with COPD severity, the mortality association was attenuated by using different methods of tighter confounding control: the IRRs were 1.26 (95% CI, 0.97-1.64) among LABA-naïve LABA/LAMA users without recent COPD hospitalisation; 1.27 (95% CI, 1.03-1.57) in a population with additional trimming from the tails of the PS distribution; and 1.32 (95% CI, 1.19-1.48) after applying overlap-weights analysis. CONCLUSIONS: Olodaterol users had a similar risk for cardiac arrhythmias or myocardial ischaemia as other LABA users. The observed excess all-cause mortality associated with olodaterol use could be due to uncontrolled channelling bias.

Effect of long-acting ß2-agonists olodaterol and formoterol on heart rate and blood pressure in chronic obstructive pulmonary disease patients.

BACKGROUND: Cardiovascular comorbidities are common in chronic obstructive pulmonary disease (COPD), and elevated heart rate reflects increased cardiovascular risk over time, which is associated with unfavourable neurohumoral activation. Long-acting ß2-agonists (LABAs) are established treatments in COPD, but potentially increase heart rate. We report a post hoc pooled analysis of the effect of olodaterol (5 or 10 µg) or formoterol (12 µg) on heart rate and blood pressure (BP) in Global Initiative for Chronic Obstructive Lung Disease Stage 2-4 COPD patients. METHODS: Four randomised, double-blind, placebo-controlled, Phase III studies were analysed. Changes in heart rate and systolic/diastolic BP were measured before and after dosing with the study medication at each visit. RESULTS: At each study visit, the increase in pre-dose heart rate was numerically lower with both LABAs compared with placebo. Systolic and diastolic BP were decreased with all treatments. Short-term (pre-dose to 40 min post-dose) effects of drug administration on heart rate were small and similar for all treatment arms (between -3 and +1 beats per minute). CONCLUSION: Heart rate and BP were not adversely influenced in this study involving long-term administration of olodaterol or formoterol in patients with moderate-to-severe COPD. This supports the cardiovascular safety of LABAs in COPD maintenance treatment.

One-Year Safety of Olodaterol Once Daily via Respimat® in Patients with GOLD 2-4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis.

The novel long-acting ß2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2-4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 µg) QD via Respimat®, formoterol 12 µg twice daily (BID) via Aerolizer® (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with ∼60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 µg, 883 received olodaterol 10 µg, 885 received placebos, and 460 received formoterol 12 µg BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 µg (marketed and registered dose) and 10 µg QD delivered via Respimat® are comparable to placebo and formoterol BID in this population, with no safety signals identified.

Chronic obstructive pulmonary disease and the risk of cardiovascular diseases.

Previous large epidemiological studies reporting on the association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases mainly focussed on prevalent diseases rather than on the incidence of newly diagnosed cardiovascular outcomes. We used the UK-based General Practice Research Database (GPRD) to assess the prevalence and incidence of cardiovascular diseases in COPD patients aged 40-79 between 1995 and 2005, and we randomly matched COPD-free comparison patients to COPD patients. In nested-case control analyses, we compared the risks of developing an incident diagnosis of cardiac arrhythmias, venous thromboembolism, myocardial infarction, or stroke between patients with and without COPD, stratifying the analyses by COPD-severity, using COPD-treatment as proxy for disease severity. We identified 35,772 patients with COPD and the same number of COPD-free patients. Most cardiovascular diseases were more prevalent among COPD patients than among the comparison group of COPD-free patients. The relative risk estimates of developing an incident diagnosis of cardiac arrhythmia (OR 1.19, 95% CI 0.98-1.43), deep vein thrombosis (OR 1.35, 95% CI 0.97-1.89), pulmonary embolism (OR 2.51, 95% CI 1.62-3.87), myocardial infarction (OR 1.40, 95% CI 1.13-1.73), or stroke (OR 1.13, 95% CI 0.92-1.38), tended to be increased for patients with COPD as compared to COPD-free controls. The findings of this large observational study provide further evidence that patients with COPD are at increased risk for most cardiovascular diseases.

Reflux disease, gastrointestinal ulcer or weight loss in patients with COPD.

Peptic ulcer disease, gastro-oesophageal reflux disease (GORD) and weight loss have been associated with chronic obstructive pulmonary disease (COPD). Many studies, especially on peptic ulcer and weight loss, are cross-sectional or were done back in the 1960s or 1970s. Our purpose was to learn more about GORD, ulcer, and weight loss in relation to COPD during long-term follow-up in recent years. We conducted a case-control and a follow-up study using the UK-based General Practice Research Database to assess and compare the prevalence and incidence of GORD, peptic ulcer and weight loss in patients with COPD and in COPD-free patients during the period 1995-2005. We identified 35,772 patients with COPD and the same number of COPD-free patients. Incidence rates of GORD, peptic ulcer and weight loss in COPD patients were 59.2, 14.8 and 134.0 per 10,000 person years, respectively. The risk of weight loss was increased in patients with COPD compared to COPD-free patients (1.81, 95% CI 1.61-2.02), while the risk of GORD (OR 1.19, 95% CI 1.00-1.40) or peptic ulcer (OR 1.24, 95% CI 0.92-1.66) were similar in both groups. The results provide further evidence that COPD is associated with weight loss, while there is no materially increased risk for ulcer or GORD associated with COPD.

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.

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).

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

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 ß2-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).

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.

Introduction: Long-acting ß2-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.

Long-term safety of tiotropium/olodaterol in older patients with moderate-to-very-severe COPD in the TONADO® studies.

Older patients with chronic obstructive pulmonary disease (COPD) may be at increased risk of adverse events (AEs) due to decreased protective organ function and increased comorbidities. TONADO® 1 + 2 were replicate, randomized, double-blind, parallel-group, 52-week, Phase III trials comparing the efficacy and safety of tiotropium/olodaterol (5/5 µg) versus the monocomponents via the Respimat® inhaler in patients with moderate-to-very-severe COPD. In this prespecified safety analysis, patients were grouped by age. Of 3100 patients, 1585 (51.1%) were aged <65 years, 1198 (38.7%) 65-<75 years, 309 (10.0%) 75-<85 years, and eight (0.3%) ≥85 years. At baseline, 23.4% had a pre-existing cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diagnosed diabetes. Overall, there was no increase in major adverse cardiac events, other AEs, or serious AEs with tiotropium/olodaterol versus the monocomponents in any age group, supporting the safety of tiotropium/olodaterol in older patients with COPD.

No Evidence of Off-label Use of Olodaterol and Indacaterol in Denmark, France, and the Netherlands: A Drug Utilization Study.

To characterize the use of olodaterol and indacaterol in clinical practice and to quantify the off-label use in asthma. Drug utilization study of new users of olodaterol or indacaterol between 2014 and 2017 in the PHARMO Database Network in the Netherlands, the Danish population registers, and the IMS Real-World Evidence Longitudinal Patient Database panels in France. On-label use was defined as use among adults with a recorded diagnosis of COPD. Off-label use was defined as use among adults with a recorded diagnosis of asthma without a recorded diagnosis of COPD or as use among patients aged ≤18 years. Potential off-label use was defined as no recorded diagnosis of either COPD or asthma. The study included 4,158 new users of olodaterol and 9,966 new users of indacaterol. Prevalence of off-label use ranged from 3.5% for both drugs to 12.4% for olodaterol and 11.9% for indacaterol. Prevalence of on-label use ranged from 47.8% to 77.7% for olodaterol and from 28.7% to 70.1% for indacaterol. The remaining new users of olodaterol and indacaterol were classified as potential off-label users, with prevalence ranging from 17.3% to 48.6% for olodaterol and from 20.5% to 66.6% for indacaterol. This study provides no evidence of a major concern in Europe for olodaterol or indacaterol for off-label use in asthma or for pediatric use.

Long-term safety of tiotropium/olodaterol Respimat® in patients with moderate-to-very severe COPD and renal impairment in the TONADO® studies.

Introduction: The safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO® studies (NCT01431274; NCT01431287). As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies. Methods: These were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat®) in patients with moderate-to-very severe COPD. In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min). Adverse events (AEs) were pooled from both studies. Results: Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment. Conclusion: Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment.

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

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).

ß-Blockers in COPD: A Cohort Study From the TONADO Research Program.

BACKGROUND: Cardiovascular disease is a frequent comorbidity in patients with COPD. Many physicians, particularly pulmonologists, are reluctant to use ß-adrenoceptor blocking agents (ß-blockers) in patients with COPD, despite their proven effectiveness in preventing cardiovascular events. METHODS: The large (5,162 patients) phase III TONADO 1 and 2 studies assessed lung function and patient-reported outcomes in patients with moderate to very severe COPD receiving long-acting bronchodilator treatment across 1 year. This post hoc analysis characterized lung-function changes, patient-reported outcomes, and safety in the subgroup of patients receiving ß-blockers in the studies. RESULTS: In total, 557 of 5,162 patients (11%) received ß-blockers at baseline. Postbronchodilator FEV1 at baseline was higher in the ß-blocker group (1.470 L) compared with that in the no ß-blocker group (1.362 L). As expected, patients receiving ß-blockers had a more frequent history of cardiovascular comorbidities and medications. Lung function improved from baseline in patients with or those without ß-blocker treatment, and no relevant between-group differences were observed in trough FEV1 or trough FVC at 24 or 52 weeks. No relevant differences were observed for St. George's Respiratory Questionnaire results and Transition Dyspnea Index in patients with ß-blockers compared with those in patients without. Safety findings were comparable between groups. CONCLUSIONS: Lung function, overall respiratory status, and safety of tiotropium/olodaterol were not influenced by baseline ß-blocker treatment in patients with moderate to very severe COPD. Results from this large patient cohort support the cautious and appropriate use of ß-blockers in patients with COPD and cardiovascular comorbidity. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01431274 and No. NCT01431287; URL: www.clinicaltrials.gov.

Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease.

BACKGROUND: Long-term safety, particularly cardiovascular safety, is of special interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting ß2-agonists and long-acting muscarinic antagonists, given potential cardiovascular effects. METHODS: Two 52-week Phase III trials (TONADO®) investigated tiotropium/olodaterol (5/5 and 2.5/5 µg) versus tiotropium 2.5, 5 µg and olodaterol 5 µg. In a pre-specified safety analysis, investigator-reported treatment-emergent adverse events (AEs), electrocardiogram and laboratory data were pooled. All serious AE (SAE) reports were reviewed by an independent Adjudication Committee, which assessed whether deaths, hospitalisations or intubations were respiratory, cardiovascular, cerebrovascular or other disease related. Subgroup analyses investigated cardiovascular safety including major cardiac events in patients with cardiovascular co-morbidities. RESULTS: This analysis comprised 3100 patients with moderate to very severe COPD, treated for ≤1 year, including 784 patients with cardiovascular co-morbidities. AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities. The incidence and nature of events were consistent with the disease under study and a 1-year trial duration. 494/3100 patients contributed to an adjudicated analysis of SAEs: 260 had respiratory-related, 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs. Incidences of these SAEs were comparable between treatments. There was no evidence of any increased risk for the combination compared to the monotherapy groups. CONCLUSIONS: These data provide confidence for clinicians that tiotropium/olodaterol 5/5 µg can be safely administered once-daily to patients with moderate to very severe COPD long-term, including those with significant cardiovascular co-morbidity. TRIAL REGISTRY: ClinicalTrials.gov, Nos.: NCT01431274, NCT01431287.

Comprehensive assessment of the safety of olodaterol 5 µg in the Respimat® device for maintenance treatment of COPD: comparison with the long-acting ß2-agonist formoterol.

This analysis provides a comprehensive clinical assessment of the long-term safety of the licensed dose of olodaterol (5 µg once daily [QD] via Respimat® inhaler) in patients with chronic obstructive pulmonary disease by exploring the occurrence of acknowledged side effects of long-acting ß2-agonists as well as those included in the olodaterol and formoterol labels. We analysed pooled data from two replicate, double-blind studies of olodaterol (5 µg QD via Respimat®) compared to formoterol (12 µg twice daily [BID]) or placebo over 48 weeks (1222.13, NCT00793624; 1222.14, NCT00796653). Patients could continue their background treatment. The analysis considered adverse events (AEs) typically associated with ß2-agonists, including cardiovascular events, as well as administration-related events. Descriptive statistics were provided for the incidence of AEs and aggregated AEs. The analysis included 1379 patients: 460 placebo, 459 olodaterol and 460 formoterol; AEs were reported by 70.9, 71.7 and 69.1% of patients, respectively. Exposure-adjusted incidence rates of cardiac AEs (arrhythmia and myocardial ischaemia) and cough were numerically lower in the olodaterol group than the formoterol group, while nasopharyngitis, throat irritation, metabolism and psychiatric disorders were numerically higher in the olodaterol group. The most frequent event in the olodaterol group was nasopharyngitis (placebo 8.0%; olodaterol 12.9%; formoterol 10.0%). Except for cough (incidence rate ratio of 0.46 [95% confidence interval 0.24, 0.89] in favour of olodaterol), there were no significant differences between active groups. In conclusion, olodaterol 5 µg QD was well tolerated over 48 weeks with a typical ß2-agonist safety profile comparable to formoterol 12 µg BID.

Lung function and long-term safety of tiotropium/olodaterol in East Asian patients with chronic obstructive pulmonary disease.

BACKGROUND AND PURPOSE: While the efficacy and safety of combined tiotropium and olodaterol in patients with COPD was established in a large clinical trial program, it is important to assess whether clinical data can be applied to geographic patient groups, particularly for East Asian patients who may have a different phenotypic profile to the global trial population. This study aimed to compare the lung function and safety profiles of tiotropium/olodaterol and monocomponents in East Asian and global populations from the TONADO® trials. MATERIALS AND METHODS: In the replicate, double-blind, parallel-group, active-controlled, randomized, 52-week, Phase III TONADO studies, patients received tiotropium/olodaterol, tiotropium, or olodaterol. We assessed the forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0-3) response and trough FEV1 response at 24 weeks for the approved doses, tiotropium/olodaterol 5/5 µg, tiotropium 5 µg, and olodaterol 5 µg. Treatment-emergent adverse events were recorded throughout treatment and ≤21 days after study medication. RESULTS: In the East Asian population, 1,152 patients were randomized (5,163 overall). After 24 weeks, FEV1 AUC0-3 and trough FEV1 responses were greater (P<0.0001) with tiotropium/olodaterol 5/5 µg in both populations versus tiotropium or olodaterol. The East Asian population showed slightly greater trough FEV1 treatment differences between tiotropium/olodaterol 5/5 µg and tiotropium compared to the overall population. Generally, no increase in adverse events was seen with tiotropium/olodaterol 5/5 µg compared to tiotropium and olodaterol in either population. CONCLUSION: The efficacy and safety profile of tiotropium/olodaterol 5/5 µg has been demonstrated for both East Asian and global populations.

Cancer risk in patients with chronic obstructive pulmonary disease.

PURPOSE: The goal of this study was to compare the risk of developing cancer between patients with or without chronic obstructive pulmonary disease (COPD), and to assess the role of gender as well as the use of respiratory medication on the risk of developing lung cancer in COPD patients. PATIENTS AND METHODS: We used the UK-based General Practice Research Database to conduct a follow-up study with a nested case-control analysis. We identified all patients with a first-time COPD diagnosis aged 40-79 years between 1995 and 2005 and a matched COPD-free comparison group. We then identified all patients who received an incident cancer diagnosis during follow-up. RESULTS: Among 35,772 COPD patients and 35,772 COPD-free patients, we identified 4506 patients with an incident cancer diagnosis, of whom 2585 (57.4%) had a previous COPD diagnosis, yielding a crude incidence rate ratio of 1.64 (95% CI 1.55-1.74). The increased risk was mainly driven by a high lung cancer risk among COPD patients, while other cancers not associated with smoking were not statistically significantly associated with an altered COPD risk. In the nested case-control analysis, the odds ratio (OR) for lung cancer associated with COPD was higher for women (OR 5.26, 95% CI 3.64-7.61) than for men (OR 2.10, 95% CI 1.70-2.60). In the nested case-control analysis, none of the respiratory drugs were associated with a substantially altered risk of developing lung cancer among COPD patients. CONCLUSION: Our findings provide further evidence that COPD is associated with an elevated lung cancer risk, and that women with COPD may be more susceptible to developing lung cancer than men. Overall, respiratory medication did not have an influence on cancer risk.

COPD and the risk of depression.

BACKGROUND: Chronic comorbidities are often associated with depression. Most previous studies exploring the association between COPD and depression were rather small and based on a cross-sectional study design. We conducted a large population-based study on the risk of developing an incident depression diagnosis in association with a previous COPD diagnosis. METHODS: We used the UK-based General Practice Research Database to assess and compare the prevalence of a history of depression and to quantify the risk of developing incident depression in patients with COPD and patients without COPD between 1995 and 2005. We conducted a nested case-control analysis, matching up to four patients who did not develop depression for each case patient with depression, to further analyze the impact of COPD severity. RESULTS: In a study population of 35,722 patients with COPD and 35,722 patients without COPD, the prevalence of diagnosed depression prior to the first COPD diagnosis was higher in the population with COPD (23.1%) than among patients without COPD (16.8%). The incidence rate of a new-onset diagnosis of depression after the first COPD diagnosis was 16.2/1,000 person-years (py) in the COPD group, whereas it was only 9.4/1,000 py in the COPD-free comparison group. In the nested case-control analysis, patients with severe COPD had the highest risk of developing depression (odds ratio, 2.01; 95% CI, 1.45-2.78). CONCLUSION: This large observational study provides further evidence that patients with COPD are at an increased risk of developing depression.