AbstractPurposeThe goal of this study was to assess the long-term safety and efficacy of mepolizumab in patients with the most severe eosinophilic asthma. MethodsThis multicenter, open-label, ...long-term, Phase IIIb study (COSMEX COSMOS Extension; 201312/NCT02135692) enrolled patients from the 52-week, open-label extension study COSMOS (A Study to Determine Long-term Safety of Mepolizumab in Asthmatic Subjects) that previously enrolled patients from the double-blinded, placebo-controlled Phase III studies MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) and SIRIUS (Steroid Reduction with Mepolizumab Study). To enter COSMEX, patients had to have life-threatening/seriously debilitating asthma before entering MENSA or SIRIUS and to have completed these previous studies with demonstrated improvement while receiving mepolizumab. In COSMEX, patients received mepolizumab 100 mg subcutaneously every 4 weeks as add-on therapy for up to 172 weeks. Primary endpoints were adverse event frequency and exacerbation rate per year; also assessed were forced expiratory volume in 1 s, Asthma Control Questionnaire-5 score, and daily oral corticosteroid (OCS) use. FindingsOf the 340 patients enrolled, 339 received mepolizumab; median treatment duration within this extension study was 2.2 years, equating to 718 patient-years of additional exposure. No new safety signals were identified. Patients receiving mepolizumab throughout this study and previous studies had lasting reductions in exacerbation rate and daily OCS use and improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire-5 score. In COSMEX, the on-treatment exacerbation rate (95% CI) was 0.93 (0.81–1.06) event/year for clinically significant exacerbations, 0.13 (0.10–0.18) event/year for exacerbations requiring hospitalization/emergency department visit, and 0.07 (0.05–0.10) event/year for exacerbations requiring hospitalization. In patients requiring systemic/oral corticosteroids with ≥128 weeks of continuous enrollment across SIRIUS, COSMOS, and COSMEX, mepolizumab maintained the median daily OCS dose at 1.3–2.8 mg during COSMEX, with additional patients no longer requiring OCS after extended mepolizumab treatment. ImplicationsThis study indicates that long-term mepolizumab treatment is well tolerated and associated with sustained clinical benefits in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT02135692.
Practice guidelines reflect published literature. Because of the ever changing literature base, it is necessary to update and revise guideline recommendations from time to time. The Society of ...Thoracic Surgeons recommends review and possible update of previously published guidelines at least every three years. This summary is an update of the blood conservation guideline published in 2007.
The search methods used in the current version differ compared to the previously published guideline. Literature searches were conducted using standardized MeSH terms from the National Library of Medicine PUBMED database list of search terms. The following terms comprised the standard baseline search terms for all topics and were connected with the logical 'OR' connector--Extracorporeal circulation (MeSH number E04.292), cardiovascular surgical procedures (MeSH number E04.100), and vascular diseases (MeSH number C14.907). Use of these broad search terms allowed specific topics to be added to the search with the logical 'AND' connector.
In this 2011 guideline update, areas of major revision include: 1) management of dual anti-platelet therapy before operation, 2) use of drugs that augment red blood cell volume or limit blood loss, 3) use of blood derivatives including fresh frozen plasma, Factor XIII, leukoreduced red blood cells, platelet plasmapheresis, recombinant Factor VII, antithrombin III, and Factor IX concentrates, 4) changes in management of blood salvage, 5) use of minimally invasive procedures to limit perioperative bleeding and blood transfusion, 6) recommendations for blood conservation related to extracorporeal membrane oxygenation and cardiopulmonary perfusion, 7) use of topical hemostatic agents, and 8) new insights into the value of team interventions in blood management.
Much has changed since the previously published 2007 STS blood management guidelines and this document contains new and revised recommendations.
Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disorder associated with increased comorbid prevalence of cardiovascular diseases. We aimed to quantify the magnitudes of ...association between overall and specific types of cardiovascular disease, major cardiovascular risk factors, and COPD.
We searched Cochrane, Medline, and Embase databases for studies published between Jan 1, 1980, and April 30, 2015, on the prevalence of cardiovascular disease and its risk factors in patients with COPD versus matched controls or random samples from the general public. We assessed associations with random-effects meta-analyses. We studied heterogeneity and biases with random-effects meta-regressions, jackknife sensitivity analyses, assessment of funnel plots, and Egger tests.
We identified 18,176 unique references and included 29 datasets in the meta-analyses. Compared with the non-COPD population, patients with COPD were more likely to be diagnosed with cardiovascular disease (odds ratio OR 2·46; 95% CI 2·02-3·00; p<0·0001), including a two to five times higher risk of ischaemic heart disease, cardiac dysrhythmia, heart failure, diseases of the pulmonary circulation, and diseases of the arteries. Additionally, patients with COPD reported hypertension more often (OR 1·33, 95% CI 1·13-1·56; p=0·0007), diabetes (1·36, 1·21-1·53; p<0·0001, and ever smoking (4·25, 3·23-5·60; p<0·0001). The associations between COPD and these cardiovascular disease types and cardiovascular disease risk factors were consistent and valid across studies. Enrolment period, age, quality of data, and COPD diagnosis partly explained the heterogeneity.
The coexistence of COPD, cardiovascular disease, and major risk factors for cardiovascular disease highlights the crucial need for the development of strategies to screen for and reduce cardiovascular risks associated with COPD.
Canadian Institutes of Health Research.
Background The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. Objective We ...explored this data set to define type 2 inflammation based on airway mucosal IL-13–driven gene expression and how this related to clinically accessible biomarkers. Methods IL-13–driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (F eno ) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Results Expression of airway mucosal CCL26, periostin, and IL-13–IVS all facilitated segregation of subjects into type 2–high and type 2–low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had F eno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of F eno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26–high status. Clinical variables did not differ between subjects with type 2–high and type 2–low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. Conclusion A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13–IVS gene expression. Use of F eno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.
Overdiagnosis of asthma in obese and nonobese adults Aaron, Shawn D; Vandemheen, Katherine L; Boulet, Louis-Philippe ...
Canadian Medical Association journal (CMAJ),
2008-Nov-18, 2008-11-18, 20081118, Letnik:
179, Številka:
11
Journal Article
Recenzirano
Odprti dostop
It is unclear whether asthma is overdiagnosed in developed countries, particularly among obese individuals, who may be more likely than nonobese people to experience dyspnea.
We conducted a ...longitudinal study involving nonobese (body mass index 20-25) and obese (body mass index >/= 30) individuals with asthma that had been diagnosed by a physician. Participants were recruited from 8 Canadian cities by means of random-digit dialing. A diagnosis of current asthma was excluded in those who did not have evidence of acute worsening of asthma symptoms, reversible airflow obstruction or bronchial hyperresponsiveness, despite being weaned off asthma medications. We stopped asthma medications in those in whom a diagnosis of asthma was excluded and assessed their clinical outcomes over 6 months.
Of 540 individuals with physician-diagnosed asthma who participated in the study, 496 (242 obese and 254 nonobese) could be conclusively assessed for a diagnosis of asthma. Asthma was ultimately excluded in 31.8% (95% confidence interval CI 26.3%-37.9%) in the obese group and in 28.7% (95% CI 23.5%-34.6%) in the nonobese group. Overdiagnosis of asthma was no more likely to occur among obese individuals than among nonobese individuals (p = 0.46). Of those in whom asthma was excluded, 65.5% did not need to take asthma medication or seek health care services because of asthma symptoms during a 6-month follow-up period.
About one-third of obese and nonobese individuals with physician-diagnosed asthma did not have asthma when objectively assessed. This finding suggests that, in developed countries such as Canada, asthma is overdiagnosed.
Background The Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ) are widely used in asthma research; however, in studies of newer asthma treatments, mean ...improvements in these measures compared with placebo arms do not exceed the minimal important difference (MID), particularly when a new treatment is added to current treatment. Objective We performed a systematic review and network meta-analysis to examine the magnitude of AQLQ and ACQ responses achieved with commonly used asthma drugs and factors influencing these end points in clinical trials. Methods A systematic literature search was conducted to identify blinded randomized controlled trials reporting AQLQ or ACQ results. Mixed treatment comparisons, combined with meta-regression, were then performed. Results Of the 64 randomized controlled trials (42,527 patients) identified, 54 included the AQLQ and 11 included the ACQ as end points. The presence of a run-in period, the nature of treatment during the run-in period, concurrent treatment during the treatment period, and instrument version significantly influenced the change in AQLQ score from baseline and whether it exceeded the MID. When compared with placebo, only inhaled corticosteroids (ICSs), with or without a long-acting β-agonist, achieved the MID. The ACQ results were comparable with those of the AQLQ: no differences from placebo exceeded the MID, and ICS-based treatments provided the greatest improvements. Conclusion The established within-patient MID for the ACQ and AQLQ is not achievable as a group-wise efficacy threshold between treatment arms in clinical studies in which controllers are added to ICS treatment. Thus in addition to reporting mean changes of the instruments, other measurement criteria should be considered, including responder analyses.
Background Adherence to evidence-based controller treatments for asthma is disappointingly low in many jurisdictions. Quantifying the burden associated with suboptimal adherence in patients with ...uncontrolled asthma will help establish the priorities for policymakers. Objective We sought to quantify the benefits in the United States of improving adherence to controller therapies in adults with uncontrolled asthma in terms of health care costs and quality-adjusted life years (QALYs). Methods A Markov model of asthma was created to simulate the effect of treatment with controller medications on asthma control and exacerbations over a 10-year time horizon. Health care costs and QALYs associated with the current level of adherence (status quo) were compared with a hypothetical scenario in which each patient with uncontrolled asthma at baseline will be fully adherent to an evidence-based controller therapy (the full-adherence scenario). We also evaluated the cost-effectiveness of adherence interventions as a function of their costs and improvement in the adherence. Results The status quo level of asthma management was associated with $2,786 costs and 7.55 QALYs over 10 years, whereas the corresponding values for the full-adherence scenario were $5,973 and 7.68, respectively. Consequently, the incremental cost-effectiveness ratio of the full-adherence versus the status quo was $24,515/QALY. To be cost-effective, a program that improves adherence by 50% should cost less than $130 ($450) per person annually at a willingness-to-pay value of $50,000/QALY ($100,000/QALY). Inclusion of productivity loss in the analysis resulted in the full-adherence scenario being cost-saving. Conclusion Considering the extent of suboptimal adherence, our study shows that attempts in improving adherence to evidence-based therapies in patients with uncontrolled asthma can be associated with significant return on investment.
Background Little is known about the natural history of chronic obstructive pulmonary disease (COPD) that has developed from airway remodeling due to asthma, as compared with other COPD phenotypes. ...Objective We compared long-term health outcomes of individuals with COPD with and without a history of asthma in a population-based cohort study. Methods All individuals with physician-diagnosed COPD between the ages 40 and 55 years from 2009 and 2011 were identified and followed until March 2013 through provincial health administrative data (Ontario, Canada). The exposure was a history of asthma at least 2 years before the diagnosis of COPD to ensure it preceded COPD. The hazards of COPD-, respiratory-, and cardiovascular (CV)-related hospitalizations and all-cause mortality were compared between groups using a Cox regression model controlling for demographic characteristics, comorbidities, and level of health care. Results Among 9053 patients with COPD, 2717 (30%) had a history of asthma. Over a median of 2.9 years, 712 (8%) individuals had a first COPD hospitalization, 964 (11%) a first respiratory-related and 342 (4%) a first CV-related hospitalization, and 556 (6%) died. Controlling for confounding, a history of asthma was significantly associated with COPD and respiratory-related hospitalizations (hazard ratio, 1.53 95% CI, 1.29-1.82 and hazard ratio, 1.63 95% CI, 1.14-1.88, respectively), but not with CV-related hospitalizations or all-cause mortality. Additional analyses confirmed that these findings were not likely a result of unmeasured confounding or misclassification. Conclusions Middle-aged individuals with physician-diagnosed COPD and a history of asthma had a higher hazard of hospitalizations due to COPD and other respiratory diseases than did those without.
AbstractObjectiveTo demonstrate the landscape of model-based economic studies in asthma and highlight where there is room for improvement in the design and reporting of studies. DesignA systematic ...review of the methodologies of model-based, cost-effectiveness analyses of asthma-related interventions was conducted. Models were evaluated for adherence to best-practice modeling and reporting guidelines and assumptions about the natural history of asthma. MethodsA systematic search of English articles was performed in MEDLINE, EMBASE, and citations within reviewed articles. Studies were summarized and evaluated based on their adherence to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). We also studied the underlying assumptions about disease progression, heterogeneity in disease course, comorbidity, and treatment effects. ResultsForty-five models of asthma were included (33 Markov models, 10 decision trees, 2 closed-form equations). Novel biological treatments were evaluated in 12 studies. Some of the CHEERS’ reporting recommendations were not satisfied, especially for models published in clinical journals. This was particularly the case for the choice of the modeling framework and reporting on heterogeneity. Only 13 studies considered any subgroups, and 2 explicitly considered the impact of comorbidities. Adherence to CHEERS requirements and the quality of models generally improved over time. ConclusionIt would be difficult to replicate the findings of contemporary model-based evaluations of asthma-related interventions given that only a minority of studies reported the essential parameters of their studies. Current asthma models generally lack consideration of disease heterogeneity and do not seem to be ready for evaluation of precision medicine technologies.
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