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1.
Artigo em Inglês | MEDLINE | ID: mdl-33447025

RESUMO

Introduction: The presence of cardiovascular (CV) risk factors and CV disease in patients with chronic obstructive pulmonary disease (COPD) leads to worse outcomes. A number of tools are currently available to stratify the risk of adverse outcomes in these patients with COPD. This post hoc analysis evaluated the Summit Lab Score for validation as a predictor of the first episode of moderate-to-severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and other outcomes, in patients with COPD and high arterial pulse wave velocity (aPWV). Methods: Data from a multicenter, randomized, placebo-controlled, double-blind study were retrospectively analyzed to evaluate treatment effects of once-daily fluticasone furoate/vilanterol 100/25 µg in patients with COPD and an elevated CV risk (aPWV≥11m/s) over 24 weeks. The previously derived Summit Lab Score and, secondarily, the Intermountain Risk Score (IMRS) were computed for each patient, with patients then stratified into tertiles for each score. Risk of moderate-to-severe AECOPD was analyzed across tertiles using Kaplan-Meier survival curve and Cox regression analyses. Results: In 430 patients with COPD, Kaplan-Meier probabilities of no moderate-to-severe AECOPD for Summit Lab Score tertiles 1, 2, and 3 were 92.3%, 95.5%, and 85.1%, respectively (P trend = 0.015), over 24 weeks. Grouped by IMRS tertiles, the respective probabilities were 92.9%, 91.2%, and 88.3%, respectively (P trend = 0.141). Length of stay in the hospital (P = 0.034) and the hospital ward (P = 0.042) were also significantly different between Summit Lab Score tertiles but not for intensive care (P = 0.191). Conclusion: The Summit Lab Score was associated with the 24-week risk of moderate-to-severe AECOPD in COPD patients with elevated CV risk. Secondarily, IMRS showed a trend towards differences in the risk of AECOPD, which was not statistically significant.

2.
Eur Respir J ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303557

RESUMO

RATIONALE: There are no validated measures of disease activity in chronic obstructive pulmonary disease (COPD). Since "active" disease is expected to have worse outcomes (e.g. mortality), we explored potential markers of disease activity in patients enrolled in the ECLIPSE cohort in relation to 8-year all-cause mortality. METHODS: We investigated: (1) how changes in relevant clinical variables over time (1 or 3 years) relate to 8-year mortality; (2) whether these variables inter-relate; and (3) if any clinical, imaging, and/or biological marker measured cross-sectionally at baseline relates to any activity component. RESULTS: Results showed that: (1) After 1 year, hospitalisation for COPD, exacerbation frequency, worsening of body mass index, airflow obstruction, dyspnoea, and exercise (BODE) index or health status (St. George's Respiratory Questionnaire [SGRQ]), and persistence of systemic inflammation were significantly associated with 8-year mortality; (2) At 3 years, the same markers, plus forced expiratory volume in 1 s (FEV1) decline and to a lesser degree computed tomography (CT) emphysema, showed association, thus qualifying as markers of disease activity; (3) Changes in FEV1, inflammatory cytokines and CT emphysema were not inter-related, while the multidimensional indices (BODE and SGRQ) showed modest correlations; and, (4) Changes in these markers could not be predicted by any baseline cross-sectional measure. CONCLUSIONS: In COPD, 1- and 3-year changes in exacerbation frequency, systemic inflammation, BODE and SGRQ scores, and FEV1 decline are independent markers of disease activity associated with 8-year all-cause mortality. These disease activity markers are generally independent and not predictable from baseline measurements.

3.
Ann Am Thorac Soc ; 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33108212

RESUMO

RATIONALE: In the Informing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy reduced exacerbation risk versus FF/VI and UMEC/VI and mortality risk versus UMEC/VI. However, pneumonia incidence was higher in the inhaled corticosteroid (FF)-containing arms raising questions about the relative benefit of exacerbation reduction compared with the increased risk of pneumonia. OBJECTIVES: Determine benefit-risk of the three treatments by evaluating time-to-first and rates of composite exacerbation or pneumonia outcomes. METHODS: We evaluated time-to-first (pre-specified) and rates (post hoc) of investigator-reported pneumonia, serious pneumonia leading to hospitalization or death, and the composite endpoints of 1) moderate (required antibiotics/corticosteroids)/severe (hospitalized) exacerbation or pneumonia and 2) severe exacerbation or serious (hospitalized) pneumonia. Analyses were repeated for radiographically confirmed pneumonia (post hoc). RESULTS: Moderate/severe exacerbations occurred in 47%, 49%, and 50% of patients randomized to FF/UMEC/VI, FF/VI and UMEC/VI, and pneumonias in 8%, 7%, and 5%, respectively. FF/UMEC/VI reduced the risk of combined moderate/severe exacerbation or pneumonia (time-to-first) versus FF/VI (hazard ratio 0.87 [95%CI 0.82-0.92]) and UMEC/VI (0.87 [0.81-0.94]), as well as the risk of combined severe exacerbation or serious pneumonia versus UMEC/VI (0.83 [0.72-0.96]). FF/UMEC/VI reduced the rate of combined moderate/severe exacerbation or pneumonia (rate ratio 0.78 [0.72-0.84]) and combined severe exacerbation or serious pneumonia (rate ratio 0.76 [0.65-0.89]) versus UMEC/VI. Results were similar for radiographically confirmed pneumonia endpoints. CONCLUSIONS: Despite higher incidence of pneumonia in FF-containing arms, these composite exacerbation/pneumonia outcomes support a favorable benefit-risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations. CLINICAL TRIAL REGISTRATION: CTT116855/NCT02164513.

4.
Ther Adv Respir Dis ; 14: 1753466620965145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33081606

RESUMO

BACKGROUND: The relationship between inhaled corticosteroids and bone mineral density (BMD) remains uncertain despite extensive research. METHODS: This was an international, multicenter, randomized, double-blind, parallel-group, 3-year noninferiority study. Patients with chronic obstructive pulmonary disease (COPD) (⩾40 years of age; smoking history ⩾10 pack years) and at least one native hip evaluable for BMD were enrolled and randomized 1:1, stratified by sex, to treatment with vilanterol (VI) 25 µg or fluticasone furoate/vilanterol (FF/VI) 100 µg/25 µg. BMD measurements were taken via dual-energy X-ray absorptiometry every 6 months. The primary endpoint was assessment of the noninferiority of change from baseline in total hip BMD per year at the -1% noninferiority level. Change from baseline in BMD at the lumbar spine and BMD measurements by sex were secondary endpoints. Incidences of COPD exacerbations and bone fractures throughout the study were also recorded. RESULTS: Of 283 randomized patients, 170 (60%) completed the study. Noninferiority was demonstrated for FF/VI versus VI with regards to change from baseline in total hip BMD per year, with changes of -0.27% and 0.18%, respectively, and a treatment difference of -0.46% per year [95% confidence interval (CI) -0.97 to 0.06]. The treatment difference for FF/VI versus VI regarding lumbar spine BMD was -0.51% per year (95% CI -1.11 to 0.10). COPD exacerbations and bone fracture rates were similar between treatment groups. CONCLUSION: FF/VI showed noninferiority to VI for change from baseline in total hip BMD per year, when assessed at the -1% noninferiority margin in a combined sample of men and women with COPD.The reviews of this paper are available via the supplemental material section.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32966751

RESUMO

BACKGROUND: Whether pharmacological therapy alters decline in forced expiratory volume in 1 second (FEV1) in chronic obstructive pulmonary disease (COPD) remains controversial. Because pharmacotherapy improves health status, exacerbation rate and symptoms, it is unethical to complete placebo-controlled long-term studies aimed at modifying FEV1 decline. OBJECTIVE: We conducted a systematic review of placebo-controlled pharmacological trials lasting ≥1 year to address the question of whether therapy alters FEV1 decline. METHODS: A literature search for randomized trials that included repeated spirometry with at least one active and one placebo arm was conducted. Articles were excluded if study duration was <1 year, <3 spirometric measurements, or <100 subjects per arm. Study design was assessed using the Jadad score. To combine studies and find the estimated effect, we used random effects methodology to account for both within-study and between-study variation. RESULTS: There were 33,051 patients in the analysis (active component, n = 21,941; placebo, n = 11,110 in 9 studies). The active treatment arms demonstrated a 5.0 mL/year reduction (95% CI, 0.8-9.1 mL/year, P < 0.001) in the rate of FEV1 decline compared with the placebo arms. The relative FEV1 differences between active and placebo arms were within the range of the differences reported for health status and for the exacerbation rate in those same studies. CONCLUSION: In COPD, pharmacotherapy ameliorates rate of lung function decline. The relative benefit observed is within the range of those reported for health status and exacerbations in the same studies. Guidelines should be adjusted according to these findings. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

6.
Int J Chron Obstruct Pulmon Dis ; 15: 1741-1750, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764918

RESUMO

Introduction: Tobacco use and other cardiovascular risk factors often accompany chronic obstructive pulmonary disease (COPD). This study derived and validated the Summit Score to predict mortality in people with COPD and cardiovascular risks. Methods: SUMMIT trial subjects (N=16,485) ages 40-80 years with COPD were randomly assigned 50%/50% to derivation (N=8181) and internal validation (N=8304). Three external COPD validations from Intermountain Healthcare included outpatients with cardiovascular risks (N=9251), outpatients without cardiovascular risks (N=8551), and inpatients (N=26,170). Cox regression evaluated 40 predictors of all-cause mortality. SUMMIT treatments including combined fluticasone furoate (FF) 100µg/vilanterol 25µg (VI) were not included in the score. Results: Mortality predictors were FEV1, heart rate, systolic blood pressure, body mass index, age, smoking pack-years, prior COPD hospitalizations, myocardial infarction, heart failure, diabetes, anti-thrombotics, anti-arrhythmics, and xanthines. Combined in the Summit Score (derivation: c=0.668), quartile 4 vs 1 had HR=4.43 in SUMMIT validation (p<0.001, 95% CI=3.27, 6.01, c=0.662) and HR=8.15 in Intermountain cardiovascular risk COPD outpatients (p<0.001, 95% CI=5.86, 11.34, c=0.736), and strongly predicted mortality in the other Intermountain COPD populations. Among all SUMMIT subjects with scores 14-19, FF 100µg/VI 25µg vs placebo had HR=0.76 (p=0.0158, 95% CI=0.61, 0.95), but FF 100µg/VI 25µg was not different from placebo for scores <14 or >19. Conclusion: In this post hoc analysis of SUMMIT trial data, the Summit Score was derived and validated in multiple Intermountain COPD populations. The score was used to identify a subpopulation in which mortality risk was lower for FF 100µg/VI 25µg treatment. Trial Registration: The SUMMIT trial is registered at ClinicalTrials.gov as number NCT01313676.

7.
Int J Chron Obstruct Pulmon Dis ; 15: 1135-1142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547001

RESUMO

Purpose: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Impaired lung function is associated with heightened risk for death, cardiovascular events, and COPD exacerbations. However, it is unclear if forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) differ in predictive value. Patients and Methods: Data from 16,485 participants in the Study to Understand Mortality and Morbidity (SUMMIT) in COPD were analyzed. Patients were grouped into quintiles for each lung function parameter (FEV1 %predicted, FVC %predicted, FEV1/FVC). The four highest quintiles (Q2-Q5) were compared to the lowest (Q1) to assess their relationship with all-cause mortality, cardiovascular events, and moderate-to-severe and severe exacerbations. Cox-regression was used, adjusted for age, sex, ethnicity, body-mass index, smoking status, previous exacerbations, cardiovascular disease, treatment, and modified Medical Research Council dyspnea score. Results: Compared to Q1 (<53.5% FEV1 predicted), increasing FEV1 quintiles (Q2 53.5-457.5% predicted, Q3 57.5-461.6% predicted, Q4 61.6-465.8% predicted, and Q5 ≥65.8%) were all associated with significantly decreased all-cause mortality (20% (4-34%), 28% (13-40%), 23% (7-36%), and 30% (15-42%) risk reduction, respectively). In contrast, a significant risk reduction (21% (4-35%)) was seen only between Q1 and Q5 quintiles of FVC. Neither FEV1 nor FVC was associated with cardiovascular risk. Increased FEV1 and FEV1/FVC quintiles were also associated with the reduction of moderate-to-severe and severe exacerbations while, surprisingly, the highest FVC quintile was related to the heightened exacerbation risk (28% (8-52%) risk increase). Conclusion: Our results suggest that FEV1 is a stronger predictor for all-cause mortality than FVC in moderate COPD patients with heightened cardiovascular risk and that subjects with moderate COPD have very different risks.

8.
BMC Pulm Med ; 20(1): 119, 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366249

RESUMO

BACKGROUND: Batefenterol (BAT) is a bi-functional molecule with both muscarinic antagonist and ß2-adrenoceptor agonist pharmacology. This Phase II, randomized, placebo-controlled, double-blind study evaluated the safety and tolerability of BAT 300 µg with fluticasone furoate (FF) 100 µg administered via the ELLIPTA inhaler (BAT/FF 300/100). METHODS: Subjects with stable chronic obstructive pulmonary disease were randomized 2:1 to receive BAT/FF 300/100 or placebo once daily for 6 weeks. The primary endpoint was change from baseline in 0-4-h weighted mean (WM) heart rate (HR, measured by electrocardiogram [ECG]) on Day 42. Other endpoints included WM and maximum 0-4-h corrected QT interval (ECG on Days 1, 28, and 42), HR measured by Holter monitoring (Day 42), and standard safety assessments. Study protocol was approved by an Investigational Review Board. RESULTS: Sixty-two patients were randomized and received ≥1 dose of study medication (BAT/FF 300/100 n = 42; placebo n = 20). Mean age was 62.5 years (standard deviation [SD] 8.17). Study completion rates were 83% (BAT/FF 300/100) and 100% (placebo). Screening mean (SD) post-bronchodilator percentage-predicted forced expiratory volume in 1 s was 57.57 (11.42) in the BAT/FF 300/100 group and 55.68 (14.03) in the placebo group. BAT/FF 300/100 was non-inferior to placebo for the primary endpoint, treatment difference: - 2.2 beats per minute (bpm), 95% confidence interval [CI]: - 6.2, 1.7). There were no clinically relevant differences between treatment groups in WM or maximum 0-4-h corrected QT interval, or mean HR based on Holter monitoring on Day 42 (BAT/FF 300/100: 76.3 bpm [SD 11.38]; placebo: 84.8 bpm [SD 9.87]). Adverse events (AEs) occurred in 38% (BAT/FF 300/100) and 35% (placebo) of patients. AEs in ≥2 subjects with BAT/FF 300/100 were dysgeusia (10%), diarrhea (7%), nasopharyngitis (7%), and cough (5%). AEs leading to discontinuation occurred in two subjects who received BAT/FF 300/100: post-treatment severe pneumonia (serious AE) and non-serious AEs of moderate vomiting and severe gastroenteritis; both were not considered drug-related. No deaths occurred. CONCLUSIONS: Six weeks of BAT/FF 300/100 treatment was non-inferior to placebo for change from baseline in HR, with no new clinically relevant general or cardiovascular safety signals. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02573870 (submitted October 12, 2015).

9.
Clin Trials ; 17(4): 430-436, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32441114

RESUMO

BACKGROUND: Adjudicated cause-specific mortality has been used in major trials of chronic obstructive pulmonary disease. However, there is less experience with adjudicated major adverse cardiovascular events as a key efficacy outcome in chronic obstructive pulmonary disease trials. The Study to Understand Mortality and Morbidity in chronic obstructive pulmonary disease trial required a Clinical Endpoint Committee to adjudicate the outcomes of modified major adverse cardiovascular events and cause-specific mortality. METHODS AND RESULTS: A six-member Clinical Endpoint Committee reviewed adverse event and serious adverse event reports included in a list of 204 Medical Dictionary for Regulatory Activities terms. Adverse events were triaged by one Clinical Endpoint Committee member, and then reviewed by three reviewers (round 1). If these three disagreed on the adjudication, the event was discussed by the full committee to reach a consensus (round 2). Among 16,485 participants, 48,105 adverse events were reported, among which 3314 were reviewed by the Clinical Endpoint Committee. After triage, 1827 were adjudicated in round 1; 338 required committee consensus in round 2, yielding 450 myocardial infarctions, strokes, unstable anginas or transient ischaemic attacks. Only 20/1627 (1%) non-serious adverse events were adjudicated as cardiovascular events. Only 45/204 Medical Dictionary for Regulatory Activities terms reviewed yielded cardiovascular events. A total of 430 deaths were adjudicated in round 1 and 631 in round 2, yielding 459 cardiovascular deaths. Adjudication of chest pain and sudden death often required additional information from site investigators. Site assessment of cardiovascular death was moderately specific (501/602 = 83%) but not sensitive (256/459 = 56%). CONCLUSION: A Clinical Endpoint Committee is useful for adjudication of major adverse cardiovascular events in chronic obstructive pulmonary disease trials but requires considerable resources and effort by investigators. This process can be streamlined by reviewing only serious adverse events and filtering by selected Medical Dictionary for Regulatory Activities terms.

11.
Am J Respir Crit Care Med ; 201(12): 1508-1516, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32162970

RESUMO

Rationale: The IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial demonstrated a significant reduction in all-cause mortality (ACM) risk with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) at risk of future exacerbations. Five hundred seventy-four patients were censored in the original analysis owing to incomplete vital status information.Objectives: Report ACM and impact of stepping down therapy, following collection of additional vital status data.Methods: Patients were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg following a run-in on their COPD therapies. Time to ACM was prespecified. Additional vital status data collection and subsequent analyses were performed post hoc.Measurements and Main Results: We report vital status data for 99.6% of the intention-to-treat population (n = 10,355), documenting 98 (2.36%) deaths on FF/UMEC/VI, 109 (2.64%) on FF/VI, and 66 (3.19%) on UMEC/VI. For FF/UMEC/VI, the hazard ratio for death was 0.72 (95% confidence interval, 0.53-0.99; P = 0.042) versus UMEC/VI and 0.89 (95% confidence interval, 0.67-1.16; P = 0.387) versus FF/VI. Independent adjudication confirmed lower rates of cardiovascular and respiratory death and death associated with the patient's COPD.Conclusions: In this secondary analysis of an efficacy outcome from the IMPACT trial, once-daily single-inhaler FF/UMEC/VI triple therapy reduced the risk of ACM versus UMEC/VI in patients with symptomatic COPD and a history of exacerbations.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Androstadienos/uso terapêutico , Álcoois Benzílicos/uso terapêutico , Clorobenzenos/uso terapêutico , Glucocorticoides/uso terapêutico , Mortalidade , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/uso terapêutico , Administração por Inalação , Idoso , Causas de Morte , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Gravidade de Doença
13.
BMJ Open Respir Res ; 6(1): e000431, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258919

RESUMO

Rationale: Systemic levels of C reactive protein (CRP), surfactant protein D (SPD), fibrinogen, soluble receptor of activated glycogen end-product (sRAGE) and club cell protein 16 (CC-16) have been associated with chronic obstructive pulmonary disease (COPD) outcomes. However, they require validation in different cohorts. Objectives: Relate systemic levels of those proteins to forced expiratory volume in 1 s (FEV1) decline, exacerbations, hospitalisations and mortality in COPD patients (FEV1 of ≥50 and ≤70% predicted) and heightened cardiovascular risk in a substudy of the Study to Understand Mortality and MorbidITy trial. Methods: Participants were randomised to daily inhalations of placebo, vilanterol 25 µg (VI), fluticasone furoate 100 µg (FF) or their combination (VI 25/FF 100) and followed quarterly until 1000 deaths in the overall 16 485 participants occurred. Biomarker blood samples were available from 1673 patients. The FEV1 decline (mL/year), COPD exacerbations, hospitalisations and death were determined. Associations between biomarker levels and outcomes were adjusted by age and gender. Results: Systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen did not relate to baseline FEV1, FEV1 decline, exacerbations or hospitalisations. Fibrinogen and CRP were related to mortality over a median follow-up of 2.3 years. Only the CC-16 changed with study therapy (VI, FF and FF/VI, p<0.01) at 3 months. Conclusions: In COPD, systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen were not associated with FEV1 decline, exacerbations or hospitalisations. These results cast doubts about the clinical usefulness of the systemic levels of these proteins as surrogate markers of these COPD outcomes. The study confirms that CRP and fibrinogen are associated with increased risk of death in patients with COPD. Trial registration number: NCT01313676.


Assuntos
Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Administração por Inalação , Idoso , Androstadienos/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Biomarcadores/sangue , Proteína C-Reativa/análise , Clorobenzenos/administração & dosagem , Quimioterapia Combinada , Estudos de Viabilidade , Feminino , Fibrinogênio/análise , Seguimentos , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/mortalidade , Proteína D Associada a Surfactante Pulmonar/sangue , Receptor para Produtos Finais de Glicação Avançada/sangue , Exacerbação dos Sintomas , Resultado do Tratamento , Uteroglobina/sangue
14.
Respir Res ; 20(1): 86, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068182

RESUMO

BACKGROUND: Platelet count is a prognostic indicator in the general population and elderly. Thrombocytosis during acute exacerbation of COPD (AECOPD) has been associated with mortality; however, the relationship between platelet count and mortality in stable COPD is unknown. METHODS: We performed post hoc secondary analysis on a subsample of 1797 patients in the Study to Understand Mortality and Morbidity in COPD (SUMMIT) who had blood samples drawn at baseline. Participants were current or former smokers, 40-80 years old with moderate COPD and history or increased risk of cardiovascular (CV) disease. The primary outcome was on and post-treatment all-cause mortality. Secondary outcomes included first-on-treatment moderate/severe AECOPD and on-treatment CV composite event (CV death, myocardial infarction, stroke, unstable angina and transient ischemic attack). Multivariable Cox proportional hazards models were used to investigate study endpoint associations with platelet count quintile grouping, continuous platelet count utilizing two-term fractional polynomials, and categories of low, normal and high platelet count (< 150, ≥150 to < 300, ≥300 × 109/L). RESULTS: Patients were followed for 2.3 ± 0.9 years for vital status and 1.6 ± 1.1 years for morbidity endpoints during which 105 (5.8%) died, 651 (36.2%) experienced AECOPD (159 with severe AECOPD) and 86 (4.8%) experienced a CV event. A U-shaped association between platelet count and all-cause mortality was observed. Compared to the third quintile group (Q3) of platelet count, risk of death was increased in the lowest quintile group (Q1; hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 0.93-3.23) and highest quintile group (Q5; HR: 1.66; 95%CI: 0.89-3.10), though point estimates were imprecise. Using clinical cutoffs, compared with normal platelet counts (≥150 to < 300 × 109/L), risk of all-cause mortality was nominally increased among patients with thrombocytopenia (HR: 1.46; 95%CI: 0.81-2.64) and high platelet count (HR: 1.66; 95%CI: 0.96-2.86). Compared with Q3, CV events were nominally increased for Q5 (HR: 1.71; 95%CI: 0.83-3.49) and Q1 (HR: 1.41; 95%CI: 0.70, 2.85). There was no association between platelet count and AECOPD. CONCLUSIONS: In stable COPD platelet count demonstrated a U-shaped association with increased risk of 3-year all-cause mortality, though a platelet count level above or below which risk of mortality was increased could not be definitively identified. TRIAL REGISTRATION: ClinicalTrials.gov NCT01313676 .


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Contagem de Plaquetas/tendências , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Mortalidade/tendências , Estudos Prospectivos , Fatores de Risco
15.
ERJ Open Res ; 5(1)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30815468

RESUMO

The impact of prior treatment on results of clinical trials in chronic obstructive pulmonary disease (COPD) has been debated. We used data from the Study to Understand Mortality and Morbidity in COPD Trial to examine the impact of prior treatment on the effects of randomised study drugs on mortality and exacerbations. We used data on 16 417 patients with moderate COPD and heightened cardiovascular risk and information on prior medications to examine the effects of fluticasone furoate (FF), vilanterol (VI) and combined FF/VI compared to placebo on moderate and severe exacerbation as well as mortality. The study was event-driven with a median study exposure of 1.8 years. This study was registered with ClinicalTrials.gov, number NCT01313676. There were no consistent associations between treatment prior to study entry and the effects of FF, VI or FF/VI on exacerbations during the study. However, patients taking inhaled corticosteroids and one or more bronchodilators prior to study entry seemed to have a better effect of active treatments than of placebo on mortality (hazard ratio for FF/VI 0.65, 95% CI 0.48-0.89). Survival in those randomised to placebo was independent of treatment prior to study enrolment. Prior treatment appears to affect treatment effects on mortality but not exacerbations in a randomised controlled trial of patients with COPD and heightened cardiovascular risk.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30880951

RESUMO

Background: Batefenterol is a novel bifunctional muscarinic antagonist ß2-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose-response of batefenterol and select a dose for Phase III development. Patients and methods: Patients aged ≥40 years with COPD and FEV1 ≥30% and ≤70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV1 over 0-6 hours post-dose and trough FEV1, analyzed by Bayesian and maximum likelihood estimation Emax of dose-response modeling, respectively, on day 42. Results: In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1-292.8 and 182.2-244.8 mL, respectively), with a relatively flat dose-response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ≥150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed. Conclusion: Batefenterol 300 µg may represent the optimal dose for Phase III studies.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Carbamatos/administração & dosagem , Inaladores de Pó Seco , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Adulto , Idoso , Carbamatos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Alemanha , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinolonas/efeitos adversos , África do Sul , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
19.
Pulm Ther ; 5(1): 81-95, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32026429

RESUMO

INTRODUCTION: This retrospective database study explored treatment patterns and potential off-label prescribing among patients newly prescribed fluticasone furoate/vilanterol (FF/VI) in a UK primary care setting. METHODS: In Europe, FF/VI is approved in two strengths: 100/25 µg for adults with chronic obstructive pulmonary disease (COPD) and 100/25 µg or 200/25 µg for treatment of asthma in patients aged 12 or older. Using electronic health records from the Clinical Practice Research Datalink, new users of FF/VI or other inhaled corticosteroid/long-acting beta-agonist fixed-dose combination products were identified and classified into one of three groups: COPD diagnosis, asthma diagnosis, and other diagnosis (not COPD or asthma). RESULTS: During 2014-2015, 4373 patients initiated FF/VI: 3380 on FF/VI 100/25 (65% in the COPD diagnosis group) and 993 on FF/VI 200/25 (51% in the asthma diagnosis group). During up to 12 months of follow-up, the median number (interquartile range) of prescriptions of the index strength issued per patient was 7 (2-8) for FF/VI 100/25 and 5 (2-8) for FF/VI 200/25; most new users did not change from the index strength prescribed (93.0% COPD; 89.7% asthma, of all patients initiating treatment with FF/VI). Potential off-label FF/VI prescribing in children < 12 years old was rare (< 0.29% in the combined asthma and other diagnosis groups), and up to one in five new users of FF/VI with COPD were potentially prescribed FF/VI 200/25 off-label during the study period. Much of the potential off-label prescribing in COPD occurred in patients with a history of asthma, those presenting with greater disease severity, and/or prior treatment with high-dose steroids. CONCLUSIONS: The prescription of FF/VI is rare in children under 12 years of age in the UK, according to our findings, but up to one in five COPD patients in the UK may have been prescribed FF/VI 200/25, some of which may have been off-label. FUNDING: This study was funded by GlaxoSmithKline plc (study 205052). STUDY REGISTRATION: GlaxoSmithKline plc Clinical Trial Registry study number 205052.

20.
J Am Coll Cardiol ; 72(10): 1126-1137, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30165984

RESUMO

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have increased risk of cardiovascular events. OBJECTIVES: This study evaluated the association between high-sensitivity cardiac troponin I concentration and cardiovascular events in patients with COPD and heightened cardiovascular risk. METHODS: In a double-blind randomized controlled trial, 16,485 patients with COPD and cardiovascular disease or risk factors were randomized to once daily inhaled placebo, fluticasone furoate (100 µg), vilanterol (25 µg), or their combination. Plasma high-sensitivity cardiac troponin I concentrations were measured in a subgroup of 1,599 patients. Outcomes were on-treatment cardiovascular events and COPD exacerbations over a median of 18 months, and cardiovascular death over a median of 27 months. RESULTS: Baseline plasma cardiac troponin I concentrations were above the limit of detection (1.2 ng/l) in 1,542 (96%) patients. Concentrations were unaffected by inhaled therapies at 3 months (p > 0.05). Compared with the lowest quintile (cardiac troponin <2.3 ng/l), patients in the highest quintile (≥7.7 ng/l) were at greater risk of cardiovascular events (hazard ratio [HR] 3.7; 95% confidence interval [CI]: 1.3 to 10.1; p = 0.012) and cardiovascular death (HR: 20.1; 95% CI: 2.4 to 165.2; p = 0.005) after adjustment for risk factors. By contrast, there were no differences in exacerbations between quintiles (HR: 1.1; 95% CI: 0.8 to 1.5; p = 0.548). CONCLUSIONS: In patients with COPD and heightened cardiovascular risk, plasma cardiac troponin I concentrations are a specific and major indicator of future cardiovascular events and cardiovascular death. Inhaled therapies did not affect cardiac troponin I concentrations consistent with their neutral effect on mortality and cardiovascular outcomes. (Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease [SUMMIT]; NCT01313676).


Assuntos
Doenças Cardiovasculares/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Troponina I/sangue , Idoso , Androstadienos/uso terapêutico , Álcoois Benzílicos/uso terapêutico , Biomarcadores/sangue , Broncodilatadores/uso terapêutico , Doenças Cardiovasculares/sangue , Clorobenzenos/uso terapêutico , Método Duplo-Cego , Feminino , Glucocorticoides/uso terapêutico , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Risco
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