Cardiovascular safety of QVA149, a combination of Indacaterol and NVA237, in COPD patients

This study assessed the cardiovascular safety of QVA149, an inhaled, once daily, bronchodilator combination containing two 24-hour bronchodilators, the long-acting β(2)-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237). In this randomised, double-blind, placebo-controlled, parallel-group study, 257 patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) were randomised to receive QVA149 (indacaterol/NVA237) 600/100 microg, 300/100 microg or 150/100 microg, indacaterol 300 μg or placebo, once daily for 14 days. The primary endpoint was change from baseline in 24-h mean heart rate versus placebo on Day 14. 255 patients were included in the safety analysis (mean age 63.8 years, 76.5% male, post-bronchodilator forced expiratory volume in one second [FEV(1)] 53.2% predicted, FEV(1)/FVC [forced vital capacity] 50.0%, mean 24-h heart rate 79.6 bpm). There were no clinically significant differences in the 24-h mean heart rate on Day 14 between the three doses of QVA149 and placebo or indacaterol. The confidence intervals of these treatment differences (contrasts) were within the pre-specified equivalence limit (-5 to 5 bpm). No clinically relevant differences in QTc interval (Fridericia's) were observed between groups on Days 1, 7 and 14. Once-daily QVA149 was well tolerated in COPD patients with a cardiovascular safety profile and overall adverse event rates similar to placebo.     

Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients

NVA237 is a novel, once daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This study aimed to assess the 24-h bronchodilatory effect following 14 days of treatment with inhaled NVA237 in patients with mild, moderate or severe COPD. This was a randomized, double-blind, placebo-controlled, two-period, crossover, multicenter study. A total of 33 patients (≥ 40 years; smoking history of ≥ 10 pack-years) were randomized to receive NVA237 50 μg once daily followed by placebo or placebo followed by NVA237 50 μg for 14 days. Treatment periods were separated by a 7-14 day washout period. The primary variable was the mean forced expiratory volume in 1 s (FEV(1)) derived from the area under the curve (AUC) between 0 and 24 h post-dose on Day 14. The 24-h FEV(1) profiles showed a consistent bronchodilator effect for NVA237 versus placebo on Day 14. Least square (LS) mean difference in FEV(1) AUC(0-24 h) values between NVA237 and placebo was 163 mL (P < 0.001). There were significant increases in mean FEV(1) AUC(0-12 h) (LS mean difference 165 mL, P = 0.001) and FEV(1) AUC(12-24 h) (161 mL, P < 0.001) versus placebo. NVA237 significantly improved peak FEV(1) (by 208 mL, P < 0.001) and trough FEV(1) (by 154 mL, P = 0.003) versus placebo on Day 14. NVA237 was well tolerated; all adverse events were mild or moderate in intensity and not related to study drug. NVA237 50 μg once daily was well tolerated and showed significant and sustained 24-h bronchodilation in patients with COPD.     

Effect of Indacaterol on Dynamic Lung Hyperinflation and Breathlessness in Hyperinflated Patients with COPD

Abstract: Indacaterol is a novel, inhaled once-daily ultra long-acting β₂-agonist for the treatment of COPD. This randomised, double-blind, placebo-controlled, two-period crossover study evaluated the effect of two-week treatment with indacaterol 300 μg on peak and isotime exercise inspiratory capacity (IC) in patients with COPD. Patients (40–80 years) with post-bronchodilator forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) <70%, percent predicted FEV₁ ≥40% and ≤80%, smoking history ≥20 pack-years and functional residual capacity >120% of predicted normal were randomised to receive indacaterol 300 μg or placebo once-daily via a single-dose dry powder inhaler. Following 14 days of treatment, IC at peak and isotime during constant-load (80% of maximum workload) cycle ergometry was analysed using linear mixed-effects models. Safety and tolerability were also monitored. Twenty-seven patients (67% male; mean age, 61.3 years) were randomised; 24 completed the study. On Day 14, indacaterol showed statistically significant improvements over placebo in peak (317 mL [95% CI: 118–517]; p < 0.01) and isotime IC (268 mL [95% CI: 104–432]; p < 0.01). Statistically significant improvements were observed with indacaterol versus placebo on Day 14 for the following secondary endpoints: resting IC, trough FEV₁, dyspnoea (BDI/TDI and Borg CR10 scale at isotime) and exercise endurance time. Indacaterol was well tolerated, with no serious adverse events or deaths. In conclusion, indacaterol 300 μg administered once-daily showed a clinically relevant increase in IC after 14 days of treatment, reflecting a reduction in dynamic hyperinflation.     

Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist,in COPD patients

NVA237 is a novel once-daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability and bronchodilator efficacy of two doses of NVA237 (100 and 200 μg), versus placebo, in patients with moderate-to-severe COPD (forced expiratory volume in 1 s [FEV₁] ≥ 30% and <80% predicted and FEV₁/forced vital capacity [FVC] < 0.7, 30 min after inhalation of 80 μg ipratropium bromide). After appropriate washout periods, patients were randomized to treatment with NVA237 100 μg (n = 92), NVA237 200 μg (n = 98) or placebo (n = 91) for 28 days. The primary objective was evaluation of safety, with efficacy measures included as secondary objectives. NVA237 was generally well tolerated and associated with a frequency and distribution of adverse events similar to placebo. Serious adverse events were uncommon and there was no evidence of adverse cardiovascular effects or unexpected events. Trough FEV₁ was significantly higher in those receiving NVA237 compared with placebo. For NVA237 100 μg the differences were 131 and 161 mL on Days 1 and 28, respectively (p < 0.05), and for NVA237 200 μg the differences were 146 and 151 mL on Days 1 and 28, respectively (p < 0.05). Peak FEV₁, FEV₁ at all timepoints up to 24 h after dosing, and FEV₁ area under the curve during 5 min–5 h post-dosing were also significantly higher in both NVA237 groups, compared with placebo. Patients receiving NVA237 required fewer daily puffs of rescue medication and had a higher percentage of days on which rescue medication was not required. Overall, the present study provides further evidence of the safety, tolerability and bronchodilator efficacy of once-daily treatment with NVA237 100 and 200 μg in patients with moderate-to-severe COPD.     

Adding a Second Bronchodilator in COPD: A Meta-Analysis on the Risk of Specific Cardiovascular Serious Adverse Events of Tiotropium/Olodaterol Fixed-Dose Combination

Abstract

Dual bronchodilation therapy represents the cornerstone for the treatment of COPD. A large retrospective study reports that adding a second long-acting bronchodilator in patients with COPD significantly increases the risk of heart failure. Nevertheless, retrospective studies are characterized by limitations including misdiagnosis and inaccuracy of recordkeeping. This study aimed to ascertain whether tiotropium/olodaterol (T/O) 5/5?μg fixed-dose combination (FDC) may modulate the risk of main cardiovascular outcomes in COPD patients enrolled in randomized controlled trials (RCTs). A meta-analysis (CRD42017070100) was performed by selecting RCTs reporting raw data from the ClinicalTrials.gov database concerning the impact of T/O 5/5?µg FDC vs. monocomponents on the occurrence of specific cardiovascular serious adverse events: arrhythmia, heart failure, myocardial infarction, and stroke. Data were reported as relative risk and 95% Confidence Interval, and the risk of publication bias assessed via Egger’s test. Eighty six full text articles were identified, and 10 RCTs published in 7 studies between 2015 and 2018 were included into the analysis. Data obtained from 12,690 COPD patients (44.47% T/O FDC, 55.53% monocomponents) were extracted. T/O 5/5?μg FDCs did not significantly modulate (p-value > 0.05) the risk of arrhythmia (1.02, 0.55 - 1.92), heart failure (0.88, 0.41 - 1.92), myocardial infarction (1.15, 0.70 - 1.87), and stroke (0.98, 0.44 - 2.16) vs. monocomponents. No significant publication bias affected the effect estimates of this meta-analysis. The results of this quantitative synthesis indicate that dual bronchodilation with T/O 5/5?μg FDC is characterized by an acceptable cardiovascular safety profile in COPD patients.     

Cardiovascular disease in asthma and COPD: a population-based retrospective cross-sectional study

We conducted a large population-based retrospective cross-sectional study for determining the extent of clinically recognized chronic obstructive pulmonary disease (COPD) and asthma, and the prevalence of associated cardiovascular diseases (CVDs), using information obtained from the Health Search Database (HSD) owned by the Italian College of General Practitioners (SIMG). Our study provides further evidence that patients with the diagnosis of COPD are at increased association with the diagnosis of most CVDs. It also documents that age clusters between 35 and 54 years are those at highest association of simultaneous presence of the diagnosis of CVD and that of COPD, with a progressive significant reduction in older age clusters. Moreover, it shows that the diagnosis of asthma is modestly associated with the diagnosis of different CV morbidities.     

Real-world Safety and Efficacy of Indacaterol Maleate in Patients with Chronic Obstructive Pulmonary Disease: Evidence from the Long-term Post-marketing Surveillance in Japan

Objective Evidence concerning the safety and efficacy of indacaterol maleate in a real-life setting is limited. The objective of this post-marketing surveillance was to evaluate the real-life safety and efficacy of indacaterol maleate in Japanese patients with chronic obstructive pulmonary disease (COPD). Methods This was a 52-week post-marketing surveillance conducted between April 2012 and December 2018. The safety endpoints included the incidence of adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs). The efficacy endpoints included the physician-reported global evaluation of treatment effectiveness (GETE), change from baseline in the COPD assessment test (CAT) results, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁), and %FEV₁ following 4, 12, 26, and 52 weeks of indacaterol administration. Results Of the 1,846 enrolled patients, 1,726 were included in the safety and efficacy analyses. The mean age of the patients was 72.5 years old. Cough, pneumonia and COPD worsening were the most common AEs reported, while pneumonia (1.04%) was the most common SAE, and cough (1.68%) was the most common ADR. GETE showed that 69.70% of patients achieved an excellent/good/moderate response following indacaterol treatment. The CAT score decreased, and lung function parameters (FVC, FEV₁ and %FEV₁) improved across all the COPD stages following treatment with indacaterol. Conclusion Indacaterol showed a favorable safety and tolerability profile in Japanese patients with COPD without new safety signals observed in real-life settings. These findings demonstrated that indacaterol is an effective maintenance treatment in real-life practice for Japanese patients with COPD.     

Efficacy and Safety of a 12-week Treatment with Twice-daily Aclidinium Bromide in COPD Patients (ACCORD COPD I)

Abstract

Background: This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD. Methods: In this 12-week, double-blind, multicenter trial, patients were randomized (1:1:1) to inhaled twice-daily aclidinium 200 μg, aclidinium 400 μg, or placebo. Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12, respectively. Health status (St. George's Respiratory Questionnaire [SGRQ]), COPD symptoms (Transitional Dyspnea Index [TDI], night and early morning symptoms), and safety were also assessed. Results: A total of 561 patients (mean age, 64 ± 9 years) with a mean baseline FEV1 of 1.36 ± 0.54 L (47.2% of predicted value) were randomized. At Week 12, aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean (95% CI) trough FEV1 compared with placebo by 86 (45, 127) mL and 124 (83,164) mL, respectively, and in peak FEV1 by 146 (101, 190) mL and 192 (148, 236) mL, respectively (p ≤ 0.0001 for all). Both aclidinium doses also provided significant improvements in SGRQ, TDI and almost all COPD symptom scores compared with placebo (p < 0.05 for all). Incidences of adverse events (AEs) were similar across treatment groups. The incidence of anticholinergic AEs was low and similar across groups (dry mouth: 0.5%–1.6%; constipation: 0%-1.1%). Conclusions: Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation, health status, and COPD symptoms. Both doses were well tolerated and had safety profiles similar to placebo.

Trial Registration: This ACCORD I study (AClidinium in Chronic Obstructive Respiratory Disease I) was registered on clinicaltrials.gov (NCT00891462) as “Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)”.     

Efficacy and Safety of an Aclidinium Bromide Treatment for 12 Weeks or Longer in Patients with Moderate-To-Severe COPD: A Meta-Analysis

Background: Bronchodilators are commonly used to manage patients with stable chronic obstructive pulmonary disease (COPD). This meta-analysis assessed the efficacy of aclidinium bromide with respect to clinical events, health-related quality of life and symptom scales, pulmonary function, and safety among patients with stable COPD. Methods: A comprehensive search of MEDLINE, EMBASE, CINAHL and the Cochrane Library databases was undertaken to identify randomized controlled trials (RCTs) that compared aclidinium with placebo, treatment over at least 12 weeks. Trials were measured using either odds ratios (OR) or mean differences (MD) with 95% confidence intervals (CI). Results: Seven studies, containing 7001 patients, were included in this meta-analysis. Compared with placebo, aclidinium bromide reduced the incidence of exacerbation-related hospitalizations (OR 0.64; 95% CI 0.47 to 0.89) and improved quality of life as measured by a lower total George's Respiratory Questionnaire [SGRQ] score (MD ?2.34; 95% CI ?3.18 to ?1.51) and attenuated dyspnea symptom as assessed by changes in the Transitional Dyspnea Index [TDI] (MD 0.76; 95% CI 0.43 to 1.10). Similar changes were observed with regard to trough FEV₁ and FVC and peak FEV₁ and FVC. No significant differences were observed with regard to all-cause mortality, COPD exacerbations, non-fatal serious adverse events or cardiac adverse events. Conclusions: Aclidinium reduced the incidence of exacerbation-related hospitalizations and improved quality of life, COPD symptoms and pulmonary function. In addition, aclidinium did not increase the incidence of non-fatal serious adverse events, cardiac adverse events, or COPD exacerbations and was not associated with increased mortality.     

Safety and Efficacy of 12-Week or Longer Indacaterol Treatment in Moderate-to-Severe COPD Patients: A Systematic Review

Background

This is a meta-analysis of the safety and efficacy of indacaterol in chronic obstructive pulmonary disease (COPD) with treatment duration of ≥12 weeks.

Methods

Randomized controlled trials (RCTs) reported in English (to September 30, 2012) were identified from PubMed, the Cochrane Library, Embase, websites, reference lists, and manual searches. Two reviewers independently assessed the quality of the trials and extracted information.

Results

Five RCTs were eligible. Five involved indacaterol, two salmeterol, one formoterol, and one tiotropium. Four studies had placebos. Using trough forced expiratory volume in 1 s as a measure of therapeutic effect, indacaterol was superior to the other β2-agonists, tiotropium, and placebo at weeks 12, 26, and 52. Indacaterol had a greater effect on the transition dyspnoea index compared with placebo, formoterol, and salmeterol, but not open-label tiotropium. In reducing the as-needed use of salbutamol, indacaterol were superior to placebo, tiotropium, and formoterol, but not salmeterol (5, 95 % confidence interval (CI), –2.15, 12.15). Indacaterol improved St George’s Respiratory Questionnaire scores more than placebo and open-label tiotropium, but not formoterol. Indacaterol seemed to cause more adverse events than placebo only at a dose of 600 μg daily and a duration of 52 weeks (risk ratio 1.15; 95 % CI, 1.04, 1.26). The total and serious adverse events and adverse events leading to discontinuation were comparable with open-label tiotropium and the β2-agonists.

Conclusions

Indacaterol is effective and well-tolerated as a bronchodilator for the maintenance of moderate to severe COPD.     

Real-world Safety and Efficacy of Indacaterol/Glycopyrronium in Japanese Patients with Chronic Obstructive Pulmonary Disease: A 52-week Post-marketing Surveillance

Objective To evaluate the long-term safety and efficacy of indacaterol/glycopyrronium (IND/GLY) in patients with chronic obstructive pulmorary disease (COPD) in a real-world setting in Japan. Methods This 52-week, multicentre, post-marketing surveillance conducted in Japan between December 2013 and August 2019 included patients using IND/GLY for the first time to relieve airway obstructive disorder-related symptoms. Safety outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), and serious ADRs during the 52-week period. The incidence of priority variables, including cardiovascular/cerebrovascular (CCV) AEs, β-adrenergic-related or anticholinergic AEs and cough, was also assessed. Safety outcomes were also evaluated in elderly patients. Efficacy outcomes included a physician''s global assessment, COPD assessment test (CAT) and lung function test. Results Of the 1,167 patients registered, 1,108 were included in the safety and efficacy analysis. In the safety analysis population, the incidence of AEs was 13.54%, that of SAEs was 4.69%, that of ADR was 3.61%, and that of serious ADRs was 0.36% over 52 weeks. CCV AEs, β-adrenergic-related and anticholinergic AEs and cough were reported as 2.62%, 1.99% and 0.63%, respectively. The physician''s global assessment showed that the overall response rate at the last assessment was 74.19%. The mean (95% confidence interval) CAT scores decreased from the start of treatment to Week 52 with IND/GLY [-6.9 (-7.8 to -6.1)]. The lung function (FEV₁ and FVC) improved over time from the start of IND/GLY to Week 52. Conclusion IND/GLY demonstrated a good long-term safety profile in a real-world setting in Japanese patients with COPD, with beneficial effects in terms of the lung function and symptoms in clinical use.     

Trends and Cardiovascular Co-morbidities of COPD Patients in the Veterans Administration Medical System, 1991–1999

Persons with Chronic Obstructive Pulmonary Disease (COPD) are at risk for developing other smoking-related complications, including cardiac and vascular diseases. Information about the prevalence and incidence of these conditions is needed to anticipate their occurrence in clinical research. We conducted a cohort study using longitudinal administrative data to describe the prevalence and incidence of cardiovascular (CV) diseases among COPD patients treated by the Veterans Administration Medical System. The COPD cohort included all persons with a diagnosis of COPD admitted to a Veterans Administration Medical System hospital (N = 70,679) or seen in a outpatient clinic (N = 314,209) in fiscal year 1998. Each COPD patient was matched to a Veteran of the same age and gender who did not have a COPD diagnosis, creating a non-COPD cohort for comparison. Among all hospitalized Veterans, the prevalence of COPD steadily increased from 1991 to 1999, although the total number of Veterans hospitalized during this time period decreased by more than one-third. Among COPD patients hospitalized in 1998, the prevalence of coronary artery disease, congestive heart failure, and atrial fibrillation were very high (33.6%, 24.4%, and 14.3%, respectively) and significantly higher than those seen among the matched non-COPD cohort (27.1%, 13.5%, and 10.4%; p < 0.001). Among COPD outpatients, increased complications were found in every CV disease category with rate ratios that were greater than observed among inpatients. We conclude that CV diseases are remarkably prevalent among Veterans with COPD, and their incidence is likely to increase as the Veteran population ages.     

Safety and Tolerability of Nebulized Amoxicillin-Clavulanic Acid in Patients with COPD (STONAC 1 and STONAC 2)

The safety and tolerability of nebulized amoxicillin clavulanic acid were determined in patients with stable COPD and during severe exacerbations of COPD. Nine stable COPD patients received doses ranging from 50:10 mg up to 300:60 mg amoxicillin clavulanic acid and eight patients hospitalised for a COPD exacerbation received fixed doses 200/40 mg twice daily. Safety was evaluated by spirometry before and after inhalation. Tolerability was evaluated by questionnaire. Plasma and expectorated sputum samples were assayed for amoxicillin content.

Seventeen patients underwent in total 100 nebulizations with amoxicillin clavulanic acid. In this safety and tolerability study no clinically relevant deteriorations in FEV₁ were observed. Nebulized amoxicillin clavulanic acid produces sputum concentrations well above the Minimal Inhibiting Concentration of 90% for potential pathogenic micro-organisms, with low concentrations in the central compartment (low systemic exposure).

Based on spirometry and reported side effects, inhalation of nebulized amoxicillin clavulanic acid seems to be safe and well tolerated, both in stable patients with COPD as in those experiencing a severe exacerbation. Levels of amoxicillin were adequate.     

沙美特罗替卡松联合噻托溴铵吸入治疗中重度COPD 40例疗效观察

目的观察沙美特罗替卡松（舒利迭）联合噻托溴铵粉吸入剂（思力华）对中重度COPD的治疗效果。方法将40例临床诊断为中重度COPD的患者随机分为两组。A组：22例,舒利迭（50/500 ug）吸人,每天2次,加用思力华,使用吸入装置（HandiHaler）吸入,每次1粒胶囊（18 ug）,每天1次。B组：18例,单纯舒利迭（50/500 ug）吸人,每天2次.疗程3个月。观察两组患者治疗前后呼吸困难的评分、血气分析及肺功能情况。结果治疗3个月后,所有患者呼吸困难均减轻,但A组呼吸困难下降值明显高于B组（P〈0.001）。与B组比较,治疗后A组肺功能指标（FVC、FEV1及FEV1/FVC）及血气指标（SaO2、PaO2）明显升高,而PaCO2则明显下降（P〈0.01）。结论长效抗胆碱药噻托溴铵与舒利迭联合应用可明显改善中重度COPD患者的呼吸困难、血气和肺功能,优于单纯应用舒利迭,可使COPD得到良好的控制。     

Patterns of Physical Activity Progression in Patients With COPD

IntroductionAlthough mean physical activity in COPD patients declines by 400–500 steps/day annually, it is unknown whether the natural progression is the same for all patients. We aimed to identify distinct physical activity progression patterns using a hypothesis-free approach and to assess their determinants.MethodsWe pooled data from two cohorts (usual care arm of Urban Training [NCT01897298] and PROactive initial validation [NCT01388218] studies) measuring physical activity at baseline and 12 months (Dynaport MoveMonitor). We identified clusters (patterns) of physical activity progression (based on levels and changes of steps/day) using k-means, and compared baseline sociodemographic, interpersonal, environmental, clinical and psychological characteristics across patterns.ResultsIn 291 COPD patients (mean ± SD 68 ± 8 years, 81% male, FEV₁ 59 ± 19%_pred) we identified three distinct physical activity progression patterns: Inactive (n = 173 [59%], baseline: 4621 ± 1757 steps/day, 12-month change (Δ): −487 ± 1201 steps/day), Active Improvers (n = 49 [17%], baseline: 7727 ± 3275 steps/day, Δ: + 3378 ± 2203 steps/day) and Active Decliners (n = 69 [24%], baseline: 11 267 ± 3009 steps/day, Δ: −2217 ± 2085 steps/day). After adjustment in a mixed multinomial logistic regression model using Active Decliners as reference pattern, a lower 6-min walking distance (RRR [95% CI] 0.94 [0.90–0.98] per 10 m, P = .001) and a higher mMRC dyspnea score (1.71 [1.12–2.60] per 1 point, P = .012) were independently related with being Inactive. No baseline variable was independently associated with being an Active Improver.ConclusionsThe natural progression in physical activity over time in COPD patients is heterogeneous. While Inactive patients relate to worse scores for clinical COPD characteristics, Active Improvers and Decliners cannot be predicted at baseline.