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

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 ß2-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).

COPD is a complicated disease that deteriorates over time. Worsening of COPD is associated with the lungs working less effectively, a fall in quality of life and a rise in sudden flare-ups of the disease. In this study, we looked at lung function, quality of life and flare-ups together using a measure called "clinically important deterioration" (CID). We looked at 2055 people with COPD to compare the effects of taking two bronchodilators (tiotropium and olodaterol) against taking one bronchodilator (tiotropium alone). Bronchodilators are a type of inhaled medication that relax the muscles in the lungs and widen airways, making it easier to breathe. They have also been shown to reduce sudden flare-ups of COPD. Across a wide range of people with COPD, we found that treatment with tiotropium/olodaterol reduced the risk of a CID compared with tiotropium alone. This includes in those patients at an early stage of disease, who may benefit from finding the best treatment option for them as early as possible.

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

The American Thoracic Society guidelines recommend long-acting ß2-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 post hoc 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 (FEV1), 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 FEV1, SGRQ and TDI compared with tiotropium alone. The observed mean differences were: trough FEV1, 0.054 L (95% confidence interval [CI] 0.036, 0.073; p < 0.001); SGRQ, -1.918 (95% CI -2.994, -0.843; p < 0.001); and TDI, 0.575 (95% CI 0.301, 0.848; p < 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.

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.

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 ß2-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 (FEV1) < 80% predicted (lower limit FEV1 ≥ 30% in OTEMTO 1/2 only). We examined the effect of tiotropium/olodaterol 5/5 µg versus tiotropium 5 µg on trough FEV1 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 FEV1 [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 (FEV1 ≥ 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).

People with chronic obstructive pulmonary disease (COPD) often have problems breathing, which can make it difficult to carry out daily physical tasks. Bronchodilators are a type of medication that relax the muscles in the lungs and widen airways, making it easier to breathe. Evidence suggests that using a combination of two different bronchodilators is more effective than using one bronchodilator on its own.In this article, we look at four large studies that compared the effects of at least 12 weeks of treatment with two bronchodilators (tiotropium/olodaterol) with tiotropium on its own in people who had not received any previous medication for their COPD. The results suggest that people who were treated with tiotropium and olodaterol together had significantly better improvements in lung function, quality of life and breathlessness after 12 weeks than those taking tiotropium alone, without compromising safety. Overall, people treated with tiotropium/olodaterol were 60% more likely to experience a meaningful improvement in at least one of these areas compared with those on tiotropium alone. These results support the use of tiotropium and olodaterol together as a first medication for COPD.

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

INTRODUCTION: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting ß2-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 (FEV1), 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 FEV1, - 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 FEV1 (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 (FEV1 ≥ 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).

Global recommendations suggest that people with chronic obstructive pulmonary disease (COPD) can start treatment with one of two types of inhaled medicine: either a long-acting muscarinic antagonist (LAMA) or a long-acting ß₂-agonist (LABA). Doctors can also prescribe these treatments together (LAMA/LABA) if needed. To help doctors decide whether to prescribe single or combined treatment, we looked at people with COPD who were taking LAMA alone at the beginning of two large studies (TONADO^® and OTEMTO^®). In these studies, people with COPD could either stay on LAMA alone (tiotropium) or switch to combined LAMA/LABA treatment (tiotropium/olodaterol). We looked to see if there were any changes in the functioning of the lungs (measured using forced expiratory volume in 1 s), quality of life (measured using the St. George's Respiratory Questionnaire) or breathlessness (measured using the Transition Dyspnoea Index) between the start of the study and after 12 weeks of treatment. We showed that lung function, health-related quality of life and breathlessness were significantly better in people taking tiotropium/olodaterol for 12 weeks compared with those on tiotropium alone. Overall, our results support global recommendations and suggest that many people with COPD who are treated with tiotropium could benefit from stepping up to tiotropium/olodaterol.

Association Between Serum Cotinine Level and Serological Markers of Epstein-Barr Virus in Healthy Subjects in South China Where Nasopharyngeal Carcinoma Is Endemic.

Introduction: Self-reported smoking has been associated with higher seropositivity for the IgA response to Epstein-Barr virus (EBV) viral capsid antigen (VCA-IgA) and transcription activator protein (Zta) in healthy men in southern China where nasopharyngeal carcinoma (NPC) is endemic. Results on the association of biochemically verified smoking status with EBV reactivation are scarce. We aimed to investigate the relations of serum cotinine level with serological markers of EBV in healthy women, in addition to men. Methods: We collected information on demographic, lifestyle, environmental factors, and EBV serological markers in a cross-sectional study on 2,275 healthy subjects who were recruited from physical examination centers in Guangdong Province, China. In the present analysis, 901 subjects' serum cotinine levels have been measured by enzyme-linked immunosorbent assay (ELISA). Odds ratios (seropositivity of four EBV serological markers vs. seronegativity) for categorical serum cotinine levels were calculated by unconditional logistic regression with a group-specific confidence interval (CI). Results: In women, compared with lower serum cotinine level (0-0.71 ng/ml), higher cotinine level (>0.71-1.20 ng/ml; >1.20-228.40 ng/ml) was associated but non-significantly with higher seropositivity for EBV VCA-IgA (age- and education-adjusted OR = 1.18, 95% CIs = 0.84-1.64, 1.06, 0.75-1.50). These associations remained but still non-significant after adjusting for 5-year age group, education, family history of cancer, consumption of tea, Chinese herbal tea, salted fish at childhood, and exposure to occupational dust, chemical, fume, and radiation (multivariable adjusted OR = 1.21, 95% CIs = 0.85-1.71, 1.09, 0.76-1.55). In men, compared with lower serum cotinine level (0-2.15 ng/ml), higher cotinine level (>2.15-103.6 ng/ml; >103.6-419.4 ng/ml) was significantly associated with higher seropositivity for EBV VCA-IgA and Zta-IgA (age- and education-adjusted OR = 2.16, 95% CIs = 1.37-3.41, 1.79, 1.11-2.90; 1.98, 1.17-3.34, 1.95, 1.14-3.34). The association remained significant after adjusting for potential confounders for Zta-IgA (OR = 2.32, 95% CI = 1.37-3.93 for >2.15-103.6, and 2.50, 1.43-4.38 for >103.6-419.4 ng/ml), but not for VCA-IgA (2.06, 1.29-3.27, and 1.61, 0.96-2.71). Conclusions: Higher serum cotinine level is associated with higher seropositivity for EBV serological markers in healthy men in southern China. Such positive association was also observed in women but became non-significant. If confirmed to be causal, this finding has important implications for tobacco control and prevention of EBV-related disease, particularly for NPC.

Associations between environmental factors and serological Epstein-Barr virus antibodies in patients with nasopharyngeal carcinoma in South China.

Epstein-Barr virus (EBV) reactivation, reflected by aberrantly increased levels of various serological antibodies, has been suggested to be an early indicator of nasopharyngeal carcinoma (NPC) onset and progression. We have previously suggested that certain lifestyle and dietary factors were associated with elevated serological levels of the antibody against various EBV antigens namely VCA, Zta, EBNA1, and oral EBV DNA loads among healthy population. It remains unclear whether these potential environmental factors would also influence EBV serological antibodies in NPC patients. We conducted an epidemiological study to evaluate the associations between such environmental factors and EBV antibody levels among 1701 NPC patients in South China. Pretreatment serums were collected and examined for VCA-IgA and EA-IgA by immunoenzymatic assays and antienzyme rate (AER) of EBV DNase-specific neutralizing antibody. We found that consumption of Canton-style herbal tea was significantly correlated with increased serological antibody levels of VCA-IgA and EA-IgA, with adjusted ORs of 1.35 (95% CI: 1.03-1.76) and 1.32 (95% CI: 1.01-1.73), respectively, in the weekly intake frequency stratum, while not related to AER of EBV DNase-specific neutralizing antibody. Smoking was found to be not only an apparent risk factor for higher antibody levels of AER in stage III-IV patients (OR = 1.60, 95% CI: 1.11-2.30), but also associated closely with NPC stage at diagnosis (OR = 2.17, 95% CI: 1.47-3.22), with dose-response effects. In conclusion, we found consumption of Canton-style herbal tea and cigarette smoking were in positive associations with elevated EBV antibodies in NPC patients, which may be of public health significance for the primary prevention of EBV-associated diseases especially NPC.

Association of dietary fat intake with the risk of hip fractures in an elderly Chinese population: A matched case-control study.

AIM: The aim of the present study was to examine the association between dietary fat intake and the risk of hip fractures in an elderly Chinese population. METHODS: A case-control study of 646 patients with newly diagnosed hip fractures and 646 controls, matched by age (±3 years) and sex, was carried out among elderly Chinese (55-80 years) in Guangdong, China. Their dietary fat intake was measured and calculated using a 79-item food-frequency questionnaire. RESULTS: After adjusting for potential confounders, a dose-dependent increased risk of hip fractures was found to be associated with higher intakes of total fat, animal fat, saturated fatty acids and mono-unsaturated fatty acids (P for trend < 0.005). The adjusted odds ratios (95% confidence intervals) for hip fractures from a comparison of extreme quartiles were 1.92 (1.26-2.92) for total fat, 2.60 (1.70-3.99) for animal fat, 1.95 (1.30-2.93) for saturated fatty acids and 2.22 (1.46-3.39) for animal mono-unsaturated fatty acids, respectively. No significant association was observed for plant fat or polyunsaturated fatty acids (P for trend = 0.063 for plant fat and 0.174 for polyunsaturated fatty acids). CONCLUSIONS: Our findings suggest that higher consumption of total fat and animal fat rich in saturated fatty acids might increase the risk of hip fractures in elderly Chinese.

Associations between the dietary intake of antioxidant nutrients and the risk of hip fracture in elderly Chinese: a case-control study.

The role of oxidative stress in skeletal health is unclear. The present study investigated whether a high dietary intake of antioxidant nutrients (vitamins C and E, ß-carotene, animal-derived vitamin A, retinol equivalents, Zn and Se) is associated with a reduced risk of hip fracture in elderly Chinese. This 1:1 matched case-control study involved 726 elderly Chinese with hip fracture and 726 control subjects, recruited between June 2009 and May 2013. Face-to-face interviews were conducted to determine habitual dietary intakes of the above-mentioned seven nutrients based on a seventy-nine-item FFQ and information on various covariates, and an antioxidant score was calculated. After adjustment for potential covariates, dose-dependent inverse associations were observed between the dietary intake of vitamin C, vitamin E, ß-carotene, and Se and antioxidant score and the risk of hip fracture (P for trend ≤ 0·005). The OR of hip fracture for the highest (v. lowest) quartile of intake were 0·39 (95 % CI 0·28, 0·56) for vitamin C, 0·23 (95 % CI 0·16, 0·33) for vitamin E, 0·51 (95 % CI 0·36, 0·73) for ß-carotene, 0·43 (95 % CI 0·26, 0·70) for Se and 0·24 (95 % CI 0·17, 0·36) for the antioxidant score. A moderate-to-high dietary intake of retinol equivalents in quartiles 2-4 (v. 1) was found to be associated with a lower risk of hip fracture (OR range: 0·51-0·63, P< 0·05). No significant association was observed between dietary Zn or animal-derived vitamin A intake and hip fracture risk (P for trend >0·20). In conclusion, a higher dietary intake of vitamins C and E, ß-carotene, and Se and a moderate-to-high dietary intake of retinol equivalents are associated with a lower risk of hip fracture in elderly Chinese.

[A case-control study regarding tea consumption and risk of hip fractures in middle-aged and elderly Chinese].

OBJECTIVE: To assess the impact of tea consumption on the risk of osteoporotic hip fractures. METHODS: Between January 2008 and June 2012, 581 (148 males, 433 females) incident cases of hip fractures were enrolled from four hospitals in Guangdong province, with 581 sex- and age-matched (± 3 years) controls from either hospitals or communities. Face-to-face interviews were conducted to collect data pertaining to tea drinking and various covariates. RESULTS RESULTS: from univariate conditional logistic analyses showed that an inverse association was observed in tea drinking and hip fracture risk. Longer time, greater frequency and dosage of tea consumption were dose-dependently associated with lower risk of hip fractures (P-trend < 0.05). Compared to non-drinkers, the odd ratios related to regular tea drinkers, subgroups with different length, frequency, dosage, type of tea consumption were ranged between 0.54 and 0.74 (all P < 0.05). After adjustment for factors as age, daily energy intake, BMI, education levels, passive smoking, calcium supplement and physical activity, the dose-dependent associations among above said factors still remained significant. However, the strength of the association lowered slightly. The beneficial effect of tea was significant only in men but not in women. Similar effects were found in subjects with different education levels. CONCLUSION: Regular tea drinking habit might decrease the risk of osteoporotic hip fractures in the elderly males.

Dietary patterns and the risk of hip fractures in elderly Chinese: a matched case-control study.

CONTEXT: Many studies have investigated the effects of individual foods or nutrients on bone health, but limited research has focused on dietary patterns. PURPOSE: We examined the association of dietary patterns with the risk of hip fractures in elderly Chinese. DESIGN: This 1:1 age- (±3 years) and gender-matched case-control study were performed between June 2009 and June 2012. SETTING: The study was conducted in Guangdong Province, China. PARTICIPANTS: A total of 581 pairs of hip fracture incident cases and controls (71 ± 7 years) were studied. Face-to-face interviews were conducted to assess dietary intake using a 79-item food frequency questionnaire, whereas general information was collected using structured questionnaires. Dietary patterns were identified by a principal components factor analysis. Univariate and multivariate conditional logistic regression were used to analyze the association. MAIN RESULT: We identified 4 dietary patterns: healthy, prudent, traditional, and high-fat. Dose-dependent lower risks of hip fracture were observed in relation to higher scores in the healthy dietary pattern related to high fruit and vegetable intake and in the prudent pattern typified by a higher intake of nuts, mushrooms, algae, and seafood but lower in grains, whereas the same were associated with lower scores in the high-fat dietary pattern (all P trend < .05). The adjusted odds ratios (95% confidence intervals) for hip fractures, comparing the extreme tertiles of the 3 patterns, were 0.42 (0.24-0.73) for healthy, 0.51 (0.28-0.90) for prudent, and 2.25 (1.38-3.69) for high-fat. No significant association was found between the traditional dietary pattern (with a high intake of Chinese herbal tea, double stewed soup, processed meat and fish, and organ meat) and hip fracture risk. CONCLUSIONS: Our findings suggest that the consumption of a healthy or prudent dietary pattern can protect against hip fractures, whereas a high-fat pattern promotes the incidence of such fractures.