Cardiac safety of tiotropium in patients with cardiac events: a retrospective analysis of the UPLIFT® trial.

BackgroundTiotropium is an anticholinergic bronchodilator for symptom relief and reducing exacerbations with an established safety profile in patients with chronic obstructive pulmonary disease (COPD). Using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study, we re-evaluated the safety of tiotropium HandiHaler® in patients who experienced recent myocardial infarction (MI), heart failure or unstable rhythm disorder during the study.MethodsA post-hoc analysis of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, was conducted in patients who had experienced cardiac arrhythmia, MI or cardiac failure during UPLIFT® and who completed the study. Descriptive analyses were performed.ResultsMost patients experiencing cardiac events, for which they would have been excluded at baseline, remained in the trial. Kaplan-Meier analyses revealed a trend to later occurrence of cardiac SAEs with tiotropium HandiHaler® versus placebo. Patients who experienced a cardiac event and continued in UPLIFT® were not found to be at subsequently increased risk of all-cause mortality or cardiac SAEs with tiotropium treatment. Evaluation of deaths by major adverse cardiac events composite endpoints also showed that patients treated with tiotropium were not at increased risk of mortality or cardiac SAEs compared with placebo.ConclusionsRisk of cardiac events, mortality or SAEs was not increased by tiotropium in patients experiencing cardiac events for which they would have been excluded at study baseline. The findings support the cardiac safety of tiotropium HandiHaler® in patients with COPD

Discordance in investigator-reported and adjudicated sudden death in TIOSPIR

Accurate and consistent determination of cause of death is challenging in chronic obstructive pulmonary disease (COPD) patients. TIOSPIR (N=17 135) compared the safety and efficacy of tiotropium Respimat 5/2.5 µg with HandiHaler 18 µg in COPD patients. All-cause mortality was a primary end-point. A mortality adjudication committee (MAC) assessed all deaths. We aimed to investigate causes of discordance in investigator-reported and MAC-adjudicated causes of death and their impact on results, especially cardiac and sudden death. The MAC provided independent, blinded assessment of investigator-reported deaths (n=1302) and assigned underlying cause of death. Discordance between causes of death was assessed descriptively (shift tables). There was agreement between investigator-reported and MAC-adjudicated deaths in 69.4% of cases at the system organ class level. Differences were mainly observed for cardiac deaths (16.4% investigator, 5.1% MAC) and deaths assigned to general disorders including sudden death (17.4% investigator, 24.6% MAC). Reasons for discrepancies included investigator attribution to the immediate (e.g. myocardial infarction (MI)) over the underlying cause of death (e.g. COPD) and insufficient information for a definitive cause. Cause-specific mortality varies in COPD, depending on the method of assignment. Sudden death, witnessed and unwitnessed, is common in COPD and often attributed to MI without supporting evidence

Effect of tiotropium on COPD exacerbations: A systematic review

Exacerbation frequency is related to disease progression, quality of life, and prognosis in COPD. Earlier diagnosis, along with interventions aimed at preventing exacerbations and delaying progression, may help reduce the global burden of disease. Long-acting inhaled bronchodilators are effective at maintaining symptom relief and are recommended as first-choice therapy for more symptomatic patients and those at risk of exacerbation.Published (Open Access)This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text from the publisher's site

Mortality and Exacerbation Risk by Body Mass Index in Patients with COPD in TIOSPIR and UPLIFT

RATIONALE: There is an association between body mass index (BMI) and mortality in chronic obstructive pulmonary disease (COPD), with underweight individuals having higher mortality risk. Mortality and exacerbation risks among individuals with higher BMI are unclear. OBJECTIVES: To examine the relationship between BMI and adverse outcomes in COPD. METHODS: This post hoc analysis included data from TIOSPIR (Tiotropium Safety and Performance in Respimat) (N = 17,116) and tiotropium-treated patients in UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) (N = 2,986). BMI classes (underweight [BMI < 20 kg/m(2)], normal weight [BMI 20 to <25 kg/m(2)], overweight [BMI 25 to <30 kg/m(2)], obesity class I [BMI 30 to <35 kg/m(2)], obesity class II [BMI 35 to <40 kg/m(2)], and obesity class III [BMI ⩾ 40 kg/m(2)]) were examined for adjusted associations with mortality, exacerbation, and nonfatal cardiovascular event risk using over 50,000 patient-years of cumulative follow-up data. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression models. RESULTS: In TIOSPIR, obesity prevalence was 22%, overweight 32%, and underweight 12%. The proportion of females was highest in obesity classes II and III. Overweight and obese participants had better baseline lung function versus other BMI classes; underweight participants were more likely to be current smokers. Underweight participants had a significantly higher risk of death (HR, 1.88; 95% CI, 1.62–2.20; P < 0.0001) and severe exacerbations (HR, 1.31; 95% CI, 1.16–1.47; P < 0.0001) versus normal-weight participants; however, overweight and obese participants were at lower to no additional risk. Results from UPLIFT were similar to TIOSPIR. CONCLUSIONS: These results suggest that there is a strong association between body weight, COPD events, and risk of death. A holistic management approach taking into account respiratory and cardiovascular risk factors and nutritional status is needed to improve the general well-being of patients with COPD

Modulation by steroid hormones of a "sexy" acoustic signal in an Oscine species, the Common Canary Serinus canaria

The respective influence of testosterone and estradiol on the structure of the Common Canary Serinus canaria song was studied by experimentally controlling blood levels of steroid hormones in males and analyzing the consequent effects on acoustic parameters. A detailed acoustic analysis of the songs produced before and after hormonal manipulation revealed that testosterone and estradiol seem to control distinct song parameters independently. The presence of receptors for testosterone and estradiol in the brain neural pathway controlling song production strongly suggests that the observed effects are mediated by a steroid action at the neuronal level.<br>A influência da testosterona e do estradiol, respectivamente, na estrutura do canto do Canário-do-reino Serinus canaria foi estudada analisando o efeito da manipulação dos níveis sanguíneos de hormônios esteróides em machos nos parâmetros acústicos do canto. Uma analise detalhada dos cantos produzidos antes e depois da manipulação hormonal revelou que testosterona e estradiol parecem controlar independentemente parâmetros acústicos distintos. A presença de receptores para esses hormônios no circuito neuronal para controle da produção do canto sugere fortemente que os efeitos observados são mediados pela ação de esteróides a nivel neuronal

Impact of Fractional Flow Reserve Derived from Coronary Computed Tomography Angiography on Heart Team Treatment Decision-Making in Patients with Multivessel Coronary Artery Disease: Insights from the SYNTAX III REVOLUTION Trial

Background: Fractional flow reserve (FFR) is a reliable tool for the functional assessment of coronary stenoses. FFR computed tomography (CT) derived (FFRCT) has shown to be accurate, but its clinical usefulness in patients with complex coronary artery disease remains to be investigated. The present study sought to determine the impact of FFRCT on heart team's treatment decision-making and selection of vessels for revascularization in patients with 3-vessel coronary artery disease. Methods: The trial was an international, multicenter study randomizing 2 heart teams to make a treatment decision between percutaneous coronary interventions and coronary artery bypass grafting using either coronary computed tomography angiography or conventional angiography. The heart teams received the FFRCT and had to make a treatment decision and planning integrating the functional component of the stenoses. Each heart team calculated the anatomic SYNTAX score, the noninvasive functional SYNTAX score and subsequently integrated the clinical information to compute the SYNTAX score III providing a treatment recommendation, that is, coronary artery bypass grafting, percutaneous coronary intervention, or equipoise coronary artery bypass grafting-percutaneous coronary intervention. The primary objective was to determine the proportion of patients in whom FFRCT changed the treatment decision and planning. Results: Overall, 223 patients were included. Coronary computed tomography angiography assessment was feasible in 99% of the patients and FFRCT analysis in 88%. FFRCT was available for 1030 lesions (mean FFRCT value 0.64\ub113). A treatment recommendation of coronary artery bypass grafting was made in 24% of the patients with coronary computed tomography angiography with FFRCT. The addition of FFRCT changed the treatment decision in 7% of the patients and modified selection of vessels for revascularization in 12%. With conventional angiography as reference, FFRCT assessment resulted in reclassification of 14% of patients from intermediate and high to low SYNTAX score tertile. Conclusions: In patients with 3-vessel coronary artery disease, a noninvasive physiology assessment using FFRCT changed heart team's treatment decision-making and procedural planning in one-fifth of the patients

Consistent improvement in health-related quality of life with tiotropium in patients with chronic obstructive pulmonary disease: Novel and conventional responder analyses.

INTRODUCTION: Improving health-related quality of life (HRQoL) in COPD patients is an important pharmacotherapeutic objective. This study investigated the extent, consistency, and durability of tiotropium maintenance therapy impact on HRQoL in moderate-to-very severe COPD. METHODS: Patients received once-daily tiotropium 18 μg (n = 5244) or placebo (n = 4799) via HandiHaler(®) (10 trials), or once-daily tiotropium 5 μg (n = 2622) or placebo (n = 2618) via Respimat(®) inhaler (3 trials). St George's Respiratory Questionnaire (SGRQ) total scores were measured at baseline, and 6 months (13 trials) and 1 year (9 trials) from treatment start. Adjusted mean differences between treatments for change from baseline in total scores were calculated at each time-point for each trial. Responder and deteriorator rates (decrease or increase in score ≥4 units from baseline, respectively), net benefit (responder rate increase plus deteriorator rate decrease), and cumulative improvement and deterioration were determined. RESULTS: Adjusted mean total score differences between treatments for change from baseline were significant (p < 0.05) in favor of tiotropium in 10/13 trials at 6 months and in 8/9 trials at 1 year. In all trials, estimated differences in responder rates between treatments favored tiotropium (significant [p < 0.05]: 5/13 trials at 6 months; 8/9 trials at 1 year). Net benefit favored tiotropium and cumulative improvement rates were consistently greater and deterioration rates consistently lower for tiotropium versus placebo. CONCLUSIONS: Tiotropium maintenance therapy significantly and consistently improved HRQoL in moderate-to-very severe COPD patients in a durable manner. These results may provide a benchmark for assessing benefits on HRQoL of other COPD treatments

Bi-Directional Sexual Dimorphisms of the Song Control Nucleus HVC in a Songbird with Unison Song

Sexually dimorphic anatomy of brain areas is thought to be causally linked to sex differences in behaviour and cognitive functions. The sex with the regional size advantage (male or female) differs between brain areas and species. Among adult songbirds, males have larger brain areas such as the HVC (proper name) and RA (robust nucleus of the arcopallium) that control the production of learned songs. Forest weavers (Ploceus bicolor) mated pairs sing a unison duet in which male and female mates learn to produce identical songs. We show with histological techniques that the volume and neuron numbers of HVC and RA were ≥1.5 times larger in males than in females despite their identical songs. In contrast, using in-situ hybridizations, females have much higher (30–70%) expression levels of mRNA of a number of synapse-related proteins in HVC and/or RA than their male counterparts. Male-typical and female-typical sexual differentiation appears to act on different aspects of the phenotypes within the same brain areas, leading females and males to produce the same behaviour using different cellular mechanisms