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BACKGROUND: Transverse (t)-tubules drive the rapid and synchronous Ca2+ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca2+ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca2+. METHODS: HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patchclamp, Ca2+, and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure. RESULTS: Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca2+ release in the cell interior. Systolic Ca2+, ICa-L, sarcoplasmic reticulum Ca2+ content, and SERCA function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca2+ transient, the rate of Ca2+ removal, and the peak L-type Ca2+ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria. CONCLUSIONS: We show that recovery from HF restores atrial t-tubules, and this promotes recovery of ICa-L, sarcoplasmic reticulum Ca2+ content, and systolic Ca2+. We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.
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BACKGROUND: Duchenne muscular dystrophy (DMD) is a neuromuscular disease stemming from dystrophin gene mutations. Lack of dystrophin leads to progressive muscle damage and replacement of muscle with fibrotic and adipose tissue. Pamrevlumab (FG-3019), a fully human monoclonal antibody that binds to connective tissue growth factor (CTGF), is in Phase III development for treatment of DMD and other diseases. METHODS: MISSION (Study 079; NCT02606136) was an open-label, Phase II, single-arm trial of pamrevlumab in 21 non-ambulatory patients with DMD (aged≥12 years, receiving corticosteroids) who received 35-mg/kg intravenous infusions every 2 weeks for 2 years. The primary endpoint was change from baseline in percent predicted forced vital capacity (ppFVC). Secondary endpoints included other pulmonary function tests, upper limb function and strength assessments, and changes in upper arm fat and fibrosis scores on magnetic resonance imaging. RESULTS: Fifteen patients completed the trial. Annual change from baseline (SE) in ppFVC was -4.2 (0.7) (95% CI -5.5, -2.8). Rate of decline in ppFVC in pamrevlumab-treated patients was slower than observed in historical published trials of non-ambulatory patients. MISSION participants experienced slower-than-anticipated muscle function declines compared with natural history and historical published trials of non-ambulatory patients with DMD. Pamrevlumab was well-tolerated. Treatment-emergent adverse events were mild to moderate, and none led to study discontinuation. CONCLUSIONS: nti-CTGF therapy with pamrevlumab represents a potential treatment for DMD. The lack of internal control group limits the results.
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Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/genética , Distrofina , Anticorpos Monoclonais/uso terapêutico , Fator de Crescimento do Tecido ConjuntivoRESUMO
The treatment paradigm for locally advanced pancreatic cancer (LAPC) is evolving rapidly. The development of neoadjuvant therapies composed of combination therapies and the evaluation of their impact on conversion to borderline resectable (BR) status, resection, and ultimately overall survival (OS) are presently being pursued. These efforts justify re-visiting study endpoints in order to better predict therapeutic effects on OS, by capturing not only the achievement of R0 resection at the end of induction therapy but also the long-term reductions in the rate of local and distal recurrence. The proposed herein event-free survival (EFS) endpoint, with its novel definition specific to LAPC, is formulated to achieve these objectives. It is an analog to disease-free survival (DFS) endpoint in the adjuvant setting applied to the neoadjuvant setting and may be a valuable surrogate endpoint for this patient population.
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AIMS: Methoxy polyethylene glycol-epoetin beta (continuous erythropoietin receptor activator, C.E.R.A.) is used for the treatment of anaemia in adults with chronic kidney disease (CKD). Patients treated with shorter-acting erythropoiesis-stimulating agents up to three times weekly can be switched to once-monthly C.E.R.A.. Doses can be adjusted on a monthly basis based on haemoglobin (Hb) levels during the preceding period. A model-based approach was applied to optimise C.E.R.A. development, more specifically the confirmatory trial of the paediatric plan. METHODS: Pharmacokinetic and pharmacodynamic data from a phase II paediatric study and phase II and III adult studies were analysed together using modelling and simulation to determine the pharmacokinetic/pharmacodynamic characteristics of C.E.R.A. in a broad population. Model-based simulations of C.E.R.A. treatment outcomes in paediatric patients were performed, notably when administered subcutaneously and compared to clinical and real-world data. RESULTS: Age and body weight explained differences in pharmacokinetics, while the pharmacodynamic characteristics of C.E.R.A. were similar between adult and paediatric populations. Simulated Hb levels (mean and 95% prediction interval 10.9 [10.6, 11.2] g dL-1 ) and C.E.R.A. doses (median and 95% prediction interval 105 [72, 159] µg) 20 weeks after switching to subcutaneous C.E.R.A. were confirmed by observed real-world data from International Pediatric Dialysis Network registries (mean Hb was 10.8 g dL-1 and median C.E.R.A. dose was 100 µg). CONCLUSIONS: These analyses have facilitated optimisation of the C.E.R.A. development programme in paediatric patients with anaemia of CKD to provide this patient population with faster access to the drug while avoiding unnecessary clinical trial exposure and related monitoring burden in children.
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Anemia , Eritropoetina , Hematínicos , Insuficiência Renal Crônica , Adulto , Anemia/tratamento farmacológico , Anemia/etiologia , Criança , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Desenvolvimento de Medicamentos , Hemoglobinas , Humanos , Polietilenoglicóis , Proteínas Recombinantes , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
RATIONALE: Population-based studies of idiopathic pulmonary fibrosis (IPF) in the United States have been limited by reliance on diagnostic code-based algorithms that lack clinical validation. OBJECTIVES: To validate a well-accepted International Classification of Diseases, Ninth Revision, code-based algorithm for IPF using patient-level information and to develop a modified algorithm for IPF with enhanced predictive value. METHODS: The traditional IPF algorithm was used to identify potential cases of IPF in the Kaiser Permanente Northern California adult population from 2000 to 2014. Incidence and prevalence were determined overall and by age, sex, and race/ethnicity. A validation subset of cases (n = 150) underwent expert medical record and chest computed tomography review. A modified IPF algorithm was then derived and validated to optimize positive predictive value. RESULTS: From 2000 to 2014, the traditional IPF algorithm identified 2,608 cases among 5,389,627 at-risk adults in the Kaiser Permanente Northern California population. Annual incidence was 6.8/100,000 person-years (95% confidence interval [CI], 6.1-7.7) and was higher in patients with older age, male sex, and white race. The positive predictive value of the IPF algorithm was only 42.2% (95% CI, 30.6 to 54.6%); sensitivity was 55.6% (95% CI, 21.2 to 86.3%). The corrected incidence was estimated at 5.6/100,000 person-years (95% CI, 2.6-10.3). A modified IPF algorithm had improved positive predictive value but reduced sensitivity compared with the traditional algorithm. CONCLUSIONS: A well-accepted International Classification of Diseases, Ninth Revision, code-based IPF algorithm performs poorly, falsely classifying many non-IPF cases as IPF and missing a substantial proportion of IPF cases. A modification of the IPF algorithm may be useful for future population-based studies of IPF.
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Algoritmos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/epidemiologia , Classificação Internacional de Doenças/normas , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Codificação Clínica , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Distribuição por Sexo , Estados UnidosAssuntos
Antiasmáticos/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Transtornos Cerebrovasculares/epidemiologia , Hipersensibilidade/terapia , Omalizumab/efeitos adversos , Antiasmáticos/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/mortalidade , Criança , Método Duplo-Cego , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/mortalidade , Omalizumab/uso terapêutico , Efeito Placebo , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de SobrevidaRESUMO
BACKGROUND: EXCELS, a postmarketing observational cohort study, was a commitment to the US Food and Drug Administration to assess the long-term safety of omalizumab in an observational setting, focusing predominantly on malignancies. OBJECTIVE: The aim of this study was to examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS. METHODS: Patients (≥12 years of age) with moderate to severe allergic asthma and who were being treated with omalizumab (n = 5007) or not (n = 2829) at baseline were followed up for ≤5 years. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATEs), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, and unstable angina. A prespecified analysis of the end point of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events. RESULTS: At baseline, the 2 cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus the non-omalizumab group (50% vs 23%). Omalizumab-treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1,000 person years [PYs]) than did non-omalizumab-treated patients (8.1 per 1,000 PYs). The ATE rates per 1,000 PYs were 6.66 (101 patients/15,160 PYs) in the omalizumab cohort and 4.64 (46 patients/9,904 PYs) in the non-omalizumab cohort. After control for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91-1.91). CONCLUSION: This observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus the non-omalizumab cohort. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded.
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Antiasmáticos/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Transtornos Cerebrovasculares/epidemiologia , Omalizumab/efeitos adversos , Adulto , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Omalizumab/uso terapêutico , Vigilância de Produtos Comercializados , Estudos ProspectivosRESUMO
BACKGROUND: In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV1 in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication. METHODS: Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40-80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice-web-based response system to receive lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per µL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ2 that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061. FINDINGS: 1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio [RR] 0·49 [95% CI 0·34-0·69], p<0·0001) and in the 125 mg dose group (RR 0·70 [0·51-0·95], p=0·0232) versus placebo in LAVOLTA I. Exacerbation rates were also reduced in biomarker-high patients in both dose groups versus placebo in LAVOLTA II (37·5 mg: RR 0·74 [95% CI 0·54-1·01], p=0·0609; 125 mg: RR 0·74 [0·54-1·02], p=0·0626). Pooling both studies, the proportion of patients who experienced treatment-emergent adverse events (79% [1125 of 1432 patients] for both lebrikizumab doses vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both lebrikizumab doses vs 4% [31 patients] for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group. INTERPRETATION: Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out. FUNDING: F Hoffmann-La Roche.
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Antiasmáticos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Asma/tratamento farmacológico , Eosinófilos/efeitos dos fármacos , Adulto , Idoso , Asma/sangue , Biomarcadores/sangue , Moléculas de Adesão Celular/sangue , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Second-hand smoke (SHS) exposure has been linked to the development of and morbidity from lung disease. We sought to advance understanding of the impact of SHS on health-related outcomes in individuals with COPD. METHODS: Among the participants with COPD in SPIROMICS, recent SHS exposure was quantified as (1) hours of reported exposure in the past week or (2) reported living with a smoker. We performed adjusted regression for SHS with outcomes, testing for interactions with gender, race, smoking and obesity. RESULTS: Of the 1580 participants with COPD, 20% reported living with a smoker and 27% reported exposure in the past week. Living with a smoker was associated with worse St George's Respiratory Questionnaire score (SGRQ, ß 3.10; 95% CI 0.99 to 5.21), COPD Assessment Test score (ß 1.43; 95% CI 0.52 to 2.35) and increased risk for severe exacerbations (OR 1.51, 95% CI 1.04 to 2.17). SHS exposure in the past week was associated with worse SGRQ (ß 2.52; 95% CI 0.47 to 4.58), nocturnal symptoms (OR 1.58; 95% CI 1.19 to 2.10), wheezing (OR 1.34; 95% CI 1.02 to 1.77), chronic productive cough (OR 1.77; 95% CI 1.33 to 2.35) and difficulty with cough and sputum (Ease of Cough and Sputum scale, ß 0.84; 95% CI 0.42 to 1.25). SHS was associated with increased airway wall thickness on CT but not emphysema. Active smokers, obese individuals and individuals with less severe airflow obstruction also had higher susceptibility to SHS for some outcomes. CONCLUSION: Individuals with COPD, including active smokers, have significant SHS exposure, associated with worse outcomes and airway wall thickness. Active smokers and obese individuals may have worse outcomes associated with SHS. TRIAL REGISTRATION NUMBER: NCT01969344 (clinicaltrials.gov).
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A 44-year-old man presented to the accident and emergency department with chest pain and shortness of breath. Admission ECG revealed ischaemic changes. He had markedly elevated troponin T and a severely impaired left ventricular ejection fraction with regional motion wall abnormalities. He was initially treated in intensive care for acute myocardial infarction. When his renal function improved, an angiogram was performed, which showed unobstructed coronary arteries. He was later found to have a phaeochromocytoma. This case illustrates a rare diagnosis presenting with common symptoms that could easily have been missed. On admission to hospital, patients can easily be labelled with a diagnosis and put on a treatment pathway, such as acute coronary syndrome. It is important for clinicians to keep an open mind and be prepared to review the diagnosis if the history does not fit.
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Neoplasias das Glândulas Suprarrenais/diagnóstico , Epinefrina/fisiologia , Feocromocitoma/diagnóstico , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Angina Pectoris/diagnóstico , Diagnóstico Diferencial , Dispneia/etiologia , Eletrocardiografia , Humanos , Imageamento por Ressonância Magnética , Masculino , Infarto do Miocárdio/diagnóstico , Resultado do Tratamento , Troponina T/metabolismoRESUMO
INTRODUCTION: IJS launched best evidence topic reviews (BETs) in 2011, when the guidelines for conducting and reporting these reviews were published in the journal. AIMS: (1) Audit the adherence of all published BETs in IJS to these guidelines. (2) Assess the reach and impact of BETs published in IJS. METHODS: BETs published between 2011 and February 2014 were identified from http://www.journal-surgery.net/. Standards audited included: completeness of description of study attrition, and independent verification of searches. Other extracted data included: relevant subspecialty, duration between searches and publication, and between acceptance and publication. Each BET's number of citations (http://scholar.google.co.uk/), number of tweets (http://www.altmetric.com/) and number of Researchgate views (https://www.researchgate.net/) were recorded. RESULTS: Thirty-four BETs were identified: the majority, 19 (56%), relating to upper gastrointestinal surgery and none to cardiothoracic, orthopaedic or paediatric surgery. Twenty-nine BETs (82%) fully described study attrition. Twenty-one (62%) had independently verified search results. The mean times from literature searching to publication and acceptance to publication were 38.5 weeks and 13 days respectively. There were a mean 40 (range 0-89) Researchgate views/article, mean 2 (range 0-7) citations/article and mean 0.36 (range 0-2) tweets/article. CONCLUSIONS: Adherence to BET guidelines has been variable. Authors are encouraged to adhere to journal guidelines and reviewers and editors to enforce them. BETs have received similar citation levels to other IJS articles. Means of increasing the visibility of published BETs such as social media sharing, conference presentation and deposition of abstracts in public repositories should be explored. More work is required to encourage more submissions from other surgical subspecialties other than gastrointestinal specialties.
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Auditoria Clínica , Procedimentos Cirúrgicos do Sistema Digestório/normas , Publicações Periódicas como Assunto/normas , HumanosRESUMO
RATIONALE: Links between occupational exposures and morbidity in individuals with established chronic obstructive pulmonary disease (COPD) remain unclear. OBJECTIVES: To determine the impact of occupational exposures on COPD morbidity. METHODS: A job exposure matrix (JEM) determined occupational exposure likelihood based on longest job in current/former smokers (n = 1,075) recruited as part of the Subpopulations and Intermediate Outcomes in COPD Study, of whom 721 had established COPD. Bivariate and multivariate linear regression models estimated the association of occupational exposure with COPD, and among those with established disease, the occupational exposure associations with 6-minute-walk distance (6MWD), the Modified Medical Research Council Dyspnea Scale (mMRC), the COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), 12-item Short-Form Physical Component (SF-12), and COPD exacerbations requiring health care utilization, adjusting for demographics, current smoking status, and cumulative pack-years. MEASUREMENTS AND MAIN RESULTS: An intermediate/high risk of occupational exposure by JEM was found in 38% of participants. In multivariate analysis, those with job exposures had higher odds of COPD (odds ratio, 1.44; 95% confidence interval, 1.04-1.97). Among those with COPD, job exposures were associated with shorter 6MWDs (-26.0 m; P = 0.006); worse scores for mMRC (0.23; P = 0.004), CAT (1.8; P = 0.003), SGRQ (4.5; P = 0.003), and SF-12 Physical (-3.3; P < 0.0001); and greater odds of exacerbation requiring health care utilization (odds ratio, 1.55; P = 0.03). CONCLUSIONS: Accounting for smoking, occupational exposure was associated with COPD risk and, for those with established disease, shorter walk distance, greater breathlessness, worse quality of life, and increased exacerbation risk. Clinicians should obtain occupational histories from patients with COPD because work-related exposures may influence disease burden.
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Exposição Ocupacional , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Idoso , Progressão da Doença , Modificador do Efeito Epidemiológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Qualidade de Vida , Fumar/epidemiologiaRESUMO
BACKGROUND: The Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) assessed the long-term safety of omalizumab in a clinical practice setting as part of a phase IV US Food and Drug Administration postmarketing commitment. OBJECTIVE: We sought to evaluate long-term safety in omalizumab-treated and nonomalizumab-treated patients. Primary outcome measures focused on assessment of malignancies. METHODS: EXCELS was a prospective observational cohort study in patients (≥12 years of age) with moderate-to-severe allergic asthma. There were 2 cohorts: omalizumab (taking omalizumab at baseline) and nonomalizumab (no history of omalizumab treatment). Primary outcomes included all confirmed, incident, study-emergent primary malignancies (malignancies), including and excluding nonmelanoma skin cancer (NMSC); all malignancies were externally adjudicated. RESULTS: The omalizumab cohort had a higher proportion of patients with severe asthma compared with the nonomalizumab cohort (50.0% vs 23.0%). Median follow-up was approximately 5 years for both cohorts. Crude malignancy rates were similar in the omalizumab and nonomalizumab cohorts, with a rate ratio of 0.84 (95% CI, 0.62-1.13) for all malignancies and 0.98 (95% CI, 0.71-1.36) for all malignancies excluding NMSC. Kaplan-Meier plots of time to first confirmed study-emergent primary malignancy were similar for the 2 treatment cohorts. Cox proportional hazards modeling, adjusting for confounders and risk factors, resulted in a hazard ratio (omalizumab vs nonomalizumab) of 1.09 (95% CI, 0.87-1.38) for all malignancies and 1.15 (95% CI, 0.83-1.59) for all malignancies excluding NMSC. CONCLUSION: Results from EXCELS suggest that omalizumab therapy is not associated with an increased risk of malignancy.
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Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Asma/tratamento farmacológico , Asma/epidemiologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/epidemiologia , Adulto , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Asma/mortalidade , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Omalizumab , Estudos Prospectivos , Risco , Neoplasias Cutâneas/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Adjustment for differing risks among patients is usually incorporated into newer payment approaches, and current risk models rely on age, sex, and diagnosis codes. It is unknown the extent to which controlling additionally for disease severity improves cost prediction. Failure to adjust for within-disease variation may create incentives to avoid sicker patients. We address this issue among patients with chronic obstructive pulmonary disease (COPD). METHODS: Cost and clinical data were collected prospectively from 1202 COPD patients at Kaiser Permanente. Baseline analysis included age, sex, and diagnosis codes (using the Diagnostic Cost Group Relative Risk Score) in a general linear model predicting total medical costs in the following year. We determined whether adding COPD severity measures-forced expiratory volume in 1 second, 6-Minute Walk Test, dyspnea score, body mass index, and BODE Index (composite of the other 4 measures)-improved predictions. Separately, we examined household income as a cost predictor. RESULTS: Mean costs were $12,334/y. Controlling for Relative Risk Score, each ½ SD worsening in COPD severity factor was associated with $629 to $1135 in increased annual costs (all P<0.01). The lowest stratum of forced expiratory volume in 1 second (<30% normal) predicted $4098 (95% confidence interval, $576-$8773) additional costs. Household income predicted excess costs when added to the baseline model (P=0.038), but this became nonsignificant when also incorporating the BODE Index. CONCLUSIONS: Disease severity measures explain significant cost variations beyond current risk models, and adding them to such models appears important to fairly compensate organizations that accept responsibility for sicker COPD patients. Appropriately controlling for disease severity also accounts for costs otherwise associated with lower socioeconomic status.
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Gastos em Saúde/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica/economia , Risco Ajustado/métodos , Índice de Gravidade de Doença , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Doença Crônica , Teste de Esforço , Feminino , Volume Expiratório Forçado , Humanos , Renda , Masculino , Pessoa de Meia-Idade , Modelos Econômicos , Estudos Prospectivos , Fatores Sexuais , Estados UnidosRESUMO
Omalizumab, a recombinant humanized monoclonal antibody, is the first approved anti-immunoglobulin E (IgE) agent for the treatment of subjects with moderate to severe persistent allergic asthma that are inadequately controlled by the standard of care. The objective of this study was to quantitatively characterize relationships between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) as well as serum free IgE and airway inflammation (as measured by fractional exhaled nitric oxide [FeNO]) using population-based efficacy models. Data were collected from patients in the EXTRA trial who received omalizumab or placebo 150 to 375 mg subcutaneously every 2 or 4 weeks from week 0 to 48 with constant standard of care as background therapy. None of the covariates evaluated, including demographics, disease status, and baseline pharmacodynamic biomarkers, were significant in explaining the variability in the FEV1 or FeNO response to omalizumab. Results from the efficacy models further confirmed the current omalizumab dosing rationale based on the mean target free IgE level of 25 ng/ml and quantified the variability for the target. In addition, the resulting population models could be used to predict population FEV1 or FeNO response for omalizumab and/or other anti-IgE therapeutics for which PK-IgE models are constructed.
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Antiasmáticos/uso terapêutico , Anticorpos Anti-Idiotípicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Imunoglobulina E/sangue , Pulmão/efeitos dos fármacos , Modelos Biológicos , Adolescente , Adulto , Idoso , Antiasmáticos/administração & dosagem , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Asma/diagnóstico , Asma/imunologia , Asma/fisiopatologia , Biomarcadores/sangue , Testes Respiratórios , Criança , Simulação por Computador , Método Duplo-Cego , Esquema de Medicação , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Óxido Nítrico/metabolismo , Omalizumab , Estudos Prospectivos , Espirometria , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Omalizumab is a recombinant humanized monoclonal anti-IgE antibody approved in adults and adolescents with moderate-to-severe persistent allergic asthma inadequately controlled with inhaled corticosteroids (ICS). EXCELS is an ongoing prospective observational cohort study of approximately 5000 omalizumab-treated and >2800 non-omalizumab-treated patients aged ≥12 years. OBJECTIVE: We evaluated concomitant medication use changes (total ICS dose [including monotherapy and combination therapy, fluticasone equivalent], short-acting beta-agonists [SABA], and leukotriene modifier [LTM]) over 2 years among subsets of patients enrolled in EXCELS. METHODS: Patient subsets included "new starts" (omalizumab initiated at baseline [n = 549], "established users" (omalizumab initiated >7 days before baseline [n = 4421]), and "non-omalizumab" patients (not treated with omalizumab [n = 2867]). RESULTS: At baseline, mean ± SD total daily ICS doses were 680 ± 414 µg/d in new starts, 642 ± 431 µg/d in established users, and 548 ± 382 µg/d in non-omalizumab patients. From baseline through year 2, total ICS dose decreased in 65% of new starts (mean ± SD change, -393 ± 504 µg/d), 57% of established users (-287 ± 492 µg/d), and 54% of non-omalizumab patients (-232 ± 431 µg/d). At baseline, SABA use for new starts, established users, and non-omalizumab patients was 1.9, 1.3, and 1.4 puffs/d, respectively. At year 2, SABA use decreased in 65% of new starts, 55% of established users, and 54% of non-omalizumab patients. At year 2, LTM dose decreased in 52% of new starts, 44% of established users, and 40% of non-omalizumab patients. CONCLUSION: Omalizumab therapy initiation was associated with decreased doses of ICS, SABA, and LTM over 2 years of follow-up for the majority of patients in a "real-world" cohort study of moderate-to-severe allergic asthma patients.
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Antiasmáticos/uso terapêutico , Anticorpos Anti-Idiotípicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Administração por Inalação , Adolescente , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/uso terapêutico , Adulto , Antiasmáticos/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Antagonistas de Leucotrienos/administração & dosagem , Antagonistas de Leucotrienos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Omalizumab , Estudos Prospectivos , Adulto JovemRESUMO
Asthma has been associated with increased cardiovascular disease (CVD) risk. The authors ascertained the association of asthma with CVD and the roles that sex, concurrent allergy, and asthma medications may play in this association. They assembled a cohort of 203,595 Northern California adults with asthma and a parallel asthma-free referent cohort (matched 1:1 on age, sex, and race/ethnicity); both cohorts were followed for incident nonfatal or fatal CVD and all-cause mortality from January 1, 1996, through December 31, 2008. Each cohort was 66% female and 47% white. After adjustment for age, sex, race/ethnicity, cardiac risk factors, and comorbid allergy, asthma was associated with a 1.40-fold (95% confidence interval (CI): 1.35, 1.45) increased hazard of coronary heart disease, a 1.20-fold (95% CI: 1.15, 1.25) hazard of cerebrovascular disease, a 2.14-fold (95% CI: 2.06, 2.22) hazard of heart failure, and a 3.28-fold (95% CI: 3.15, 3.41) hazard of all-cause mortality. Stronger associations were noted among women. Comorbid allergy predicted CVD but did not synergistically increase the CVD risk associated with asthma. Only asthma patients using asthma medications (particularly those on oral corticosteroids alone or in combination) were at enhanced risk of CVD. In conclusion, asthma was prospectively associated with increased risk of major CVD. Modifying effects were noted for sex and asthma medication use but not for comorbid allergy.
Assuntos
Asma/tratamento farmacológico , Asma/epidemiologia , Transtornos Cerebrovasculares/epidemiologia , Doença das Coronárias/epidemiologia , Insuficiência Cardíaca/epidemiologia , Adulto , Algoritmos , Asma/etnologia , California/epidemiologia , Estudos de Casos e Controles , Transtornos Cerebrovasculares/classificação , Transtornos Cerebrovasculares/etnologia , Comorbidade , Intervalos de Confiança , Doença das Coronárias/classificação , Doença das Coronárias/etnologia , Feminino , Insuficiência Cardíaca/classificação , Insuficiência Cardíaca/etnologia , Humanos , Incidência , Masculino , Prevalência , Modelos de Riscos Proporcionais , Estudos Prospectivos , Risco , Fatores SexuaisRESUMO
BACKGROUND: Asthma guidelines emphasize the importance of achieving and maintaining asthma control; however, many patients with moderate to severe asthma fail to achieve adequate control. OBJECTIVE: This 2-year interim analysis evaluated the longitudinal effects of omalizumab on asthma control in patients treated in real-world clinical practice settings. METHODS: EXCELS is an ongoing observational cohort study of approximately 5000 omalizumab-treated and 2500 non-omalizumab-treated patients aged ≥12 years with moderate to severe asthma. Asthma control was measured using the Asthma Control Test (ACT) every 6 months. RESULTS: Subgroups of the omalizumab cohort included those who initiated omalizumab at baseline (new starts, n = 549) and those treated with omalizumab >7 days before baseline (established users, n = 4421). For reference, data are also presented for patients who were not receiving omalizumab prior to or at the time of enrolment (non-omalizumab, n = 2867). Over half of the new starts (54%) achieved improvement in ACT consistent with the minimally important difference (MID, defined as ≥3-point improvement) by Month 6 and this proportion increased throughout the follow-up period, reaching 62% at Month 24. Similar results were observed in patients stratified by moderate and severe asthma. Established users of omalizumab maintained asthma control throughout the observation period. CONCLUSION: Over a 2-year period, patients initiating omalizumab therapy experienced clinically relevant improvements in asthma control, which were maintained during 2 years of longitudinal follow-up. Established users of omalizumab maintained asthma control over the 2-year period with a small improvement similar to that seen in non-omalizumab users.