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The widespread use of systemic corticosteroids (SCS) in asthma is associated with significant comorbidities and mortality. A dose-response relationship for cumulative SCS exposure with most adverse outcomes began at cumulative exposures of 1.0-<2.5 g, equivalent to four lifetime SCS courses. The purpose of creating the SCS credit concept was to increase awareness of the risks of SCS exposure and to promote better therapeutic alternatives. Consuming the lifetime SCS credit of 1.5 g/yr significantly increased morbidity and mortality.
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BACKGROUND: The choice of bronchodilators for responsiveness testing (BRT) is a clinical decision according to ATS/ERS. Since January 2019 we use budesonide/formoterol for BRT in asthma at our center in Argentina. The aim was to compare budesonide/formoterol with salbutamol for BRT in stable asthmatic patients that were followed up in a short-acting beta2 agonist (SABA)-free asthma center. METHODS: From the Hospital database, we found for the same patient at least one BRT using salbutamol 200 µg and another with budesonide/formoterol 320/9 µg. RESULTS: We found similar BRT between salbutamol and budesonide/formoterol in 101 asthmatic individuals (26 males) aged 38.14 ± 16.1 yrs (mean ± Standard deviation). The absolute response was 0.18 ± 0.21 L in FEV1 after salbutamol and 0.20 ± 0.22 L in FEV1 after budesonide/formoterol. Afterwards, we showed 202 patients tested with budesonide/formoterol; the mean absolute response was 0.21 ± 0.22 L in FEV1. There were no unexpected safety findings. CONCLUSIONS: In asthmatic patients, we demonstrated similar efficacy between Budesonide/formoterol and salbutamol for BRT.
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Why not directly eradicate SABA from asthma management? The time to leave behind SABA in asthma management is now. We wasted enough time identifying the key issue in asthma morbidity and mortality. Please, eradicate SABA. https://bit.ly/3DU4mmo.
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Resumen En las últimas décadas ha habido un importante desarrollo de dispositivos inhalados (DI) que permiten aumentar la eficacia de las drogas y disminuir los eventos adversos. Su correcto uso es de fundamental importancia para el control de las enfermedades respiratorias obstructivas. En la Argentina no existen recomendaciones locales sobre el uso de los DI. Se revisó la base biofísica, indicación, ventajas y limitaciones, técnica de correcto uso, errores frecuentes, mantenimiento y limpieza de cada DI. El uso de nebulizaciones ha quedado restringido a la administración de drogas que no están disponibles en otros DI (ejemplo: tratamiento de fibrosis quística), o ante la falla de los otros DI. No deben ser usados durante la pandemia de SARS-CoV2. Los inhaladores de dosis medida (aerosol) deben ser indicados siempre con aerocámaras (AC), las que reducen la incidencia de eventos adversos y aumentan el depósito de la droga en el pulmón. Son los dispositivos de elección junto a los inhaladores de polvo seco. Los aerosoles se deben usar en pacientes que no generan flujos inspiratorios altos. Los inhaladores de polvo seco deben recomendarse en aquellos que pueden realizar flujos inspiratorios enérgicos. Se revisaron los diferentes DI en fibrosis quística y en pacientes con asistencia respiratoria mecánica. La elección del DI dependerá de varios factores: situación clínica, edad, experiencia previa, preferencia del paciente, disponibilidad de la droga y entrenamiento alcanzado con el correcto uso.
Abstract Last decades, a broad spectrum of inhaled devices (ID) had been developed to enhance efficacy and reduce adverse events. The correct use of IDs is a critical issue for controlling obstructive respiratory diseases. There is no recommendation on inhalation therapy in Argentina. This document aims to issue local recommendations about the prescription of IDs. Each device was reviewed regarding biophysical laws, indication, strength, limitations, correct technique of use, frequent mistakes, and device cleaning and maintenance. Nebulization should be restricted to drugs that are not available in other IDs (for example, for treatment of cystic fibrosis) or where other devices fail. Nebulization is not recommended during the SARS-CoV2 pandemic. A metered-dose inhaler must always be used with an aerochamber. Aerochambers reduce the incidence of adverse events and improve lung deposition. Metered-dose inhalers must be prescribed to patients who cannot generate a high inspiratory flow and dry powders to those who can generate an energetic inspiratory flow. We reviewed the use of different IDs in patients with cystic fibrosis and under mechanical ventilation. The individual choice of an ID will be based on several variables like clinical status, age, previous experience, patient preference, drug availability, and correct use of the device.
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Humanos , Asma , COVID-19 , Argentina , ARN Viral , Enfermedad Pulmonar Obstructiva Crónica , SARS-CoV-2RESUMEN
Last decades, a broad spectrum of inhaled devices (ID) had been developed to enhance efficacy and reduce adverse events. The correct use of IDs is a critical issue for controlling obstructive respiratory diseases. There is no recommendation on inhalation therapy in Argentina. This document aims to issue local recommendations about the prescription of IDs. Each device was reviewed regarding biophysical laws, indication, strength, limitations, correct technique of use, frequent mistakes, and device cleaning and maintenance. Nebulization should be restricted to drugs that are not available in other IDs (for example, for treatment of cystic fibrosis) or where other devices fail. Nebulization is not recommended during the SARS-CoV2 pandemic. A metered-dose inhaler must always be used with an aerochamber. Aerochambers reduce the incidence of adverse events and improve lung deposition. Metered-dose inhalers must be prescribed to patients who cannot generate a high inspiratory flow and dry powders to those who can generate an energetic inspiratory flow. We reviewed the use of different IDs in patients with cystic fibrosis and under mechanical ventilation. The individual choice of an ID will be based on several variables like clinical status, age, previous experience, patient preference, drug availability, and correct use of the device.
En las últimas décadas ha habido un importante desarrollo de dispositivos inhalados (DI) que permiten aumentar la eficacia de las drogas y disminuir los eventos adversos. Su correcto uso es de fundamental importancia para el control de las enfermedades respiratorias obstructivas. En la Argentina no existen recomendaciones locales sobre el uso de los DI. Se revisó la base biofísica, indicación, ventajas y limitaciones, técnica de correcto uso, errores frecuentes, mantenimiento y limpieza de cada DI. El uso de nebulizaciones ha quedado restringido a la administración de drogas que no están disponibles en otros DI (ejemplo: tratamiento de fibrosis quística), o ante la falla de los otros DI. No deben ser usados durante la pandemia de SARS-CoV2. Los inhaladores de dosis medida (aerosol) deben ser indicados siempre con aerocámaras (AC), las que reducen la incidencia de eventos adversos y aumentan el depósito de la droga en el pulmón. Son los dispositivos de elección junto a los inhaladores de polvo seco. Los aerosoles se deben usar en pacientes que no generan flujos inspiratorios altos. Los inhaladores de polvo seco deben recomendarse en aquellos que pueden realizar flujos inspiratorios enérgicos. Se revisaron los diferentes DI en fibrosis quística y en pacientes con asistencia respiratoria mecánica. La elección del DI dependerá de varios factores: situación clínica, edad, experiencia previa, preferencia del paciente, disponibilidad de la droga y entrenamiento alcanzado con el correcto uso.
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Asma , COVID-19 , Enfermedad Pulmonar Obstructiva Crónica , Argentina , Humanos , ARN Viral , SARS-CoV-2RESUMEN
Resumen Introducción: A nivel mundial, la mortalidad por asma sigue siendo un tema no resuelto a pesar de existir tratamientos muy eficaces. Esto mismo ocurre en Argentina, donde también se dispone de tratamientos efectivos, pero se desconoce si existe vinculación entre mortalidad por asma y las ventas de medicación inhalatoria. El objetivo fue analizar las ventas en farmacias de medicación para enfermedades respira torias obstructivas y las muertes por asma, antes y después de la aparición de los corticosteroides inhalados (ICS) y sus combinaciones. Materiales y métodos: Los datos de mortalidad por asma de 1983 a 2018 en Argentina se obtuvieron de un informe oficial. Todos los datos sobre ventas en farmacias fueron brindados por la misma fuente (IQVIA Solutions Argentina), pero no hay datos de ventas desde 1990 a 1999. Resultados: El promedio ± desvío standard del cociente entre el total de ventas de broncodilatadores agonistas β2 adrenérgicos de acción corta (SABA) sobre total de ventas de ICS y sus combinaciones fue 13,68 ± 2,85 entre 1983-1988 y 1,03 ± 0,12 entre 2010 a 2019 (p < 0.0001). Hubo una significativa correlación entre los cocientes SABA/ICS y el número de muertes por asma desde 1983 a 2018 (correlación de Pearson: r = 0,977, p < 0,0001). Durante el período 2010 a 2018 hubo una significativa caída en las muertes comparado con 1980-1989 (145,9 ± 28,58 vs 43,1 ± 5,2; p < 0,0001). Las ventas de SABA mostraron una declinación a partir del 2016 y fueron superados por las combinaciones de ICS/ Broncodilatadores de acción prolongada (LABA) en 2019. Conclusiones: La significativa correlación entre el cociente de ventas SABA/ICS y las muertes por asma haría replantear el estereotipo de tratamiento muy arraigado del uso de SABA en el manejo de asma.
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Enfermedades Pulmonares Obstructivas , Asma , Mortalidad , Comercialización de MedicamentosRESUMEN
Abstract Introduction: Global asthma mortality is still an unresolved issue, despite the existence of highly effective treatments. This occurs in Argentina, where there are also some effective treatments, but there is few information about the relationship between asthma mortality and sales of inhaled medication. The purpose of this study was to analyze sales in pharmacies of medication for obstructive respiratory diseases and asthma deaths, before and after the appearance of inhaled corticosteroids (ICSs) and their combinations. Materials and Methods: An official bulletin was the source document for data about asthma mortality in Argentina between 1983 and 2018. All data on pharmacy sales were provided by the same source (IQVIA Solutions Argentina), but there are no sales data from 1990 to 1999. Results: The mean ± standard deviation of the ratio between total sales of short-acting β2-adrenergic agonist bronchodilators (SABAs) over total sales of ICS and their combinations was 13.68 ± 2.85 between 1983-1988 and 1.03 ± 0.12 between 2010-2019 (p < 0.0001). There was a significant correlation between the SABA/ICS ratios and the number of asthma deaths from 1983 to 2018 (Pearson correla tion: r = 0.977, p < 0.0001). During the period from 2010 to 2018 there was a significant decrease in the number of deaths compared to 1980-1989 (145.9 ± 28.58 vs. 43.1 ± 5.2; p <0.0001). Since 2016, SABA sales started to decrease and were overtaken in 2019 by the combinations of ICS/long-acting b2-agonist bronchodilators (LABAs). Conclusions: The significant correlation between the SABA/ICS sales ratio and asthma deaths would make us rethink the long-established treatment stereotype of SABAs for the management of asthma.
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Enfermedades Pulmonares Obstructivas , Asma , Mortalidad , Comercialización de MedicamentosRESUMEN
After 25 years of GINA, we need an overarching strategy. The resounding changes in GINA 2019 should be accompanied by another major change in general strategy of asthma management. The concept of control asthma and step strategy was established in 1997 by GINA; but still there is a great gap between GINA objectives and outcomes. O'Byrne and colleagues proposed a continuum of care approach; where patient-adjusted therapy would comprise both a controller and reliever (usually ICS/fast-acting LABA) in a single inhaler. We use a similar approach in our asthma centre.
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Corticoesteroides/uso terapéutico , Agonistas Adrenérgicos beta/uso terapéutico , Asma/tratamiento farmacológico , Asma/fisiopatología , Broncodilatadores/uso terapéutico , Administración por Inhalación , Corticoesteroides/administración & dosificación , Agonistas Adrenérgicos beta/administración & dosificación , Antiasmáticos/uso terapéutico , Broncodilatadores/administración & dosificación , Preparaciones de Acción Retardada , Quimioterapia Combinada , Humanos , Atención Dirigida al Paciente , Guías de Práctica Clínica como Asunto , Atención Primaria de Salud , Índice de Severidad de la EnfermedadRESUMEN
Recognition that about half of asthma deaths might be preventable if recommended guidelines are followed suggests that better implementation of established management strategies is needed. However, to achieve a further substantive reduction in asthma mortality, novel strategies will also be required. It is well established that asthma is a disease of chronic inflammation, with episodes of worsening inflammation associated with increased symptoms and/or exacerbations; however, current guidelines paradoxically recommend that initial treatment is only symptomatic, rather than directed at the underlying inflammatory mechanism. The "Treat to target" (TTT) approach has become a popular concept in the medical management of several common chronic conditions, including rheumatoid arthritis (RA), diabetes, hypertension and hyperlipidemia. For example, as part of a TTT approach, rheumatologists recommend methotrexate for RA with onset within 6 months. Applying the TTT approach to asthma, the primary target could be clinical remission and the primary goals as follows: eliminate symptoms and exacerbation risk; prevent airway remodeling; and normalize lung function. To construct a TTT algorithm for chronic asthma, the proposal is to eradicate short-acting ß2-agonists (SABA) at all asthma severity levels and replace SABA with "Anti-Inflammatory Reliever Therapy" (AIR), using inhaled corticosteroids (ICS)/SABA or ICS/formoterol. For individuals with equal to or less than 12 months' history of symptoms, fewer than two symptoms per month, no exacerbations in the last 12 months and normal lung function, the recommendation is early initiation of ICS/SABA or ICS/formoterol as AIR.
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Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Algoritmos , Antiinflamatorios/uso terapéutico , Broncodilatadores/uso terapéutico , Fumarato de Formoterol/uso terapéutico , Humanos , Inducción de Remisión , Índice de Severidad de la EnfermedadRESUMEN
In this brief communication, it was described the overreliance link generated between a young asthmatic subject and Short Acting Beta agonist (SABA) bronchodilator. It was an attempt to delineate the stages of this conflicting link where predominated the overreliance on SABA that might be one of the main circumstances surrounding near fatal asthma attack. New approach is needed from international guidelines to avoid development of such a problematic link between asthmatic subjects and SABA.
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Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Adolescente , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Adulto , Antiasmáticos/administración & dosificación , Antiasmáticos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Respiratoria , Adulto JovenRESUMEN
Tuberculosis (TB) caused by Mycobacterium tuberculosis is a health problem worldwide. Patients with pulmonary TB show a neuro-immune-endocrine imbalance characterized by an impaired cellular immunity together with increased plasma levels of cortisol, pro- and anti-inflammatory cytokines and markedly decreased dehydroepiandrosterone (DHEA) levels. Extending these findings, we now investigated the immune-endocrine profile of TB patients undergoing specific treatment. Patients (n = 24) were bled at diagnosis (T0), 2, 4, 6 months after treatment initiation and 3 months following its completion. At T0, TB patients showed increased plasma levels of interleukin-6 (IL-6), C reactive protein, interferon-gamma (IFN-γ) and transforming growth factor beta (TGF-ß). These mediators decreased during treatment, reaching levels similar to those from healthy controls (n = 26). Specific treatment led to an increased lymphoproliferative response along with clinical improvement. Newly diagnosed patients had low levels of DHEA, with increased cortisol amounts and cortisol/DHEA ratio, which normalized upon specific treatment. As regards glucocorticoid receptors (GR), TB patients at diagnosis presented a reduced mRNA GRα/GRß ratio in their peripheral blood mononuclear cells. Furthermore, multivariate analysis showed that cortisol/DHEA ratio was positively associated with inflammatory mediators for which this ratio may constitute a disease biomarker. Anti-mycobacterial treatment results in a better immune-endocrine scenario for the control of physiopathological processes accompanying disease development and hence implied in clinical recovery.
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Antituberculosos/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Leucocitos Mononucleares/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Proteína C-Reactiva/genética , Proteína C-Reactiva/inmunología , Estudios de Casos y Controles , Deshidroepiandrosterona/sangre , Etambutol/uso terapéutico , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Hidrocortisona/sangre , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Isoniazida/uso terapéutico , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/patogenicidad , Pirazinamida/uso terapéutico , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/inmunología , Rifampin/uso terapéutico , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología , Resultado del Tratamiento , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patologíaRESUMEN
Las exacerbaciones de asma pueden ser graves y ponen en riesgo la vida de los pacientes. En estos casos es fundamental reconocer signos y síntomas de riesgo, incluyendo la medición de la obstrucción al flujo aéreo y la oximetría de pulso, con la finalidad de objetivar la gravedad de la crisis. La administración adecuada del tratamiento incluyendo broncodilatadores, corticoesteroides y oxigenoterapia permite revertir la obstrucción bronquial y preservar la vida del paciente. A pesar de estas premisas básicas en el manejo de la crisis asmática, en nuestro medio se ha detectado recurrentemente una atención defciente de estos eventos. El contar con recomendaciones de fácil implementación, adecuadas a las necesidades locales y desarrolladas por médicos especialistas en medicina respiratoria podría mejorar la calidad de atención de estos pacientes. Con este objetivo se realizó una revisión bibliográfica clasificando la información según el grado de evidencia. Los resultados fueron evaluados por un panel de expertos y se desarrolló un algoritmo de manejo del asma aguda. El algoritmo propone una evaluación inicial en base a signos de severidad, datos de medición del flujo aéreo (FEV1 y/o FPE) y oximetría de pulso que permitirán clasificar las exacerbaciones según su grado de severidad e indicar detalladamente los pasos terapéuticos a seguir en cada caso, como así también los criterios de internación y alta. El uso de estas recomendaciones permitirá una mejor distribución de recursos y optimización del tratamiento de los pacientes atendidos por exacerbaciones de asma.
Asthma exacerbations can be severe and life threatening. In order to assess in a correct and objective way the severity of the exacerbation, it is essential to recognize risk signs and symptoms, including the measurement of airflow obstruction and pulse oximetry. Proper treatment including bronchodilators, corticosteroids, and oxygen can reverse bronchial obstruction and preserve patient's life. Despite these basic facts, inappropriate care in the management of acute asthma events is frequent in Argentina. Recommendations developed by specialists in respiratory medicine, which are easy to implement and adapted to local needs, could improve the quality of care of these patients. In order to accomplish these goals, an exhaustive review of the literature was conducted and the information was classified according to the degree of evidence. The results were evaluated by a panel of experts and an algorithm for the management of acute asthma was designed. This algorithm proposes an initial assessment based on asthma severity including measurement of airflow obstruction (FEV1 and/or PF) and pulse oximetry. Thus, it allows classifying exacerbations by degree of severity, leading to appropriate sequential therapeutic options as well as criteria for admission and discharge. The use of these recommendations is intended to allow a correct management of asthma exacerbations in Argentina and an optimized use of medical resources.
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Asma , TerapéuticaRESUMEN
The CODE questionnaire (COPD detection questionnaire), a simple, binary response scale (yes/no), screening questionnaire, was developed for the identification of patients with chronic obstructive pulmonary disease (COPD). We conducted a survey of 468 subjects with a smoking history in 10 public hospitals in Argentina. Patients with a previous diagnosis of COPD, asthma and other respiratory illness were excluded. Items that measured conceptual domains in terms of characteristics of symptoms, smoking history and demographics data were considered. 96 (20.5%) subjects had a diagnosis of COPD according to the 2010 Global Initiative for Chronic Obstructive Lung Disease strategy document. The variables selected for the final questionnaire were based on univariate and multivariate analyses and clinical criteria. Finally, we selected the presence or absence of six variables (age ≥50â years, smoking history ≥30â pack-years, male sex, chronic cough, chronic phlegm and dyspnoea). Of patients without any of these six variables (0 points), none had COPD. The ability of the CODE questionnaire to discriminate between subjects with and without COPD was good (the area under the receiver operating characteristic curve was 0.75). Higher scores were associated with a greater probability of COPD. The CODE questionnaire is a brief, accurate questionnaire that can identify smoking individuals likely to have COPD.
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Obstrucción de las Vías Aéreas/diagnóstico , Pulmón/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Fumar/efectos adversos , Encuestas y Cuestionarios , Adulto , Obstrucción de las Vías Aéreas/etiología , Obstrucción de las Vías Aéreas/fisiopatología , Área Bajo la Curva , Argentina/epidemiología , Distribución de Chi-Cuadrado , Femenino , Encuestas Epidemiológicas , Hospitales Públicos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Valor Predictivo de las Pruebas , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Curva ROC , Medición de Riesgo , Factores de Riesgo , Fumar/epidemiología , EspirometríaRESUMEN
BACKGROUND: Both long-acting beta2-agonists (LABA) and inhaled corticosteroids (ICS) have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their coadministration in a combination inhaler may facilitate adherence to medication regimens and improve efficacy. OBJECTIVES: To determine the efficacy and safety of combined ICS and LABA for stable COPD in comparison with placebo. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials, reference lists of included studies and manufacturers' trial registries. The date of the most recent search was June 2013. SELECTION CRITERIA: We included randomised and double-blind studies of at least four weeks' duration. Eligible studies compared combined ICS and LABA preparations with placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study risk of bias and extracted data. Dichotomous data were analysed as fixed-effect odds ratios (OR) or rate ratios (RR) with 95% confidence intervals (95% CI), and continuous data as mean differences with 95% confidence intervals. MAIN RESULTS: Nineteen studies met the inclusion criteria (with 10,400 participants randomly assigned, lasting between 4 and 156 weeks, mean 42 weeks). Studies used three different combined preparations (fluticasone/salmeterol, budesonide/formoterol or mometasone/formoterol). The studies were generally at low risk of bias for blinding but at unclear or high risk for attrition bias because of participant dropouts. Compared with placebo, both fluticasone/salmeterol and budesonide/formoterol reduced the rate of exacerbations. Mometasone/formoterol reduced the number of participants experiencing one or more exacerbation. Pooled analysis of the combined therapies indicated that exacerbations were less frequent when compared with placebo (Rate Ratio 0.73; 95% CI 0.69 to 0.78, 7 studies, 7495 participants); the quality of this evidence when GRADE criteria were applied was rated as moderate. Participants included in these trials had on average one or two exacerbations per year, which means that treatment with combined therapy would lead to a reduction of one exacerbation every two to four years in these individuals. An overall reduction in mortality was seen, but this outcome was dominated by the results of one study (TORCH) of fluticasone/salmeterol. Generally, deaths in the smaller, shorter studies were too few to contribute to the overall estimate. Further longer studies on budesonide/formoterol and mometasone/formoterol are required to clarify whether this is seen more widely. When a baseline risk of death of 15.2% from the placebo arm of TORCH was used, the three-year number needed to treat for an additional beneficial outcome (NNTB) with fluticasone/salmeterol to prevent one extra death was 42 (95% CI 24 to 775). All three combined treatments led to statistically significant improvement in health status measurements, although the mean differences observed are relatively small in relation to the minimum clinically important difference. Furthermore, symptoms and lung function assessments favoured combined treatments. An increase in the risk of pneumonia was noted with combined inhalers compared with placebo treatment (OR 1.62, 95% CI 1.36 to 1.94), and the quality of this evidence was rated as moderate, but no dose effect was seen. The three-year NNTH for one extra case of pneumonia was 17, based on a 12.3% risk of pneumonia in the placebo arm of TORCH. Fewer participants withdrew from the combined treatment arms for adverse events or lack of efficacy. AUTHORS' CONCLUSIONS: Combined inhaler therapy led to around a quarter fewer COPD exacerbations than were seen with placebo. A significant reduction in all-cause mortality was noted, but this outcome was dominated by one trial (TORCH), emphasising the need for further trials of longer duration. Increased risk of pneumonia is a concern; however, this did not translate into increased exacerbations, hospitalisations or deaths. Current evidence does not suggest any major differences between inhalers in terms of effects, but nor is the evidence strong enough to demonstrate that all are equivalent. To permit firmer conclusions about the effects of combined therapy, more data are needed, particularly in relation to the profile of adverse events and benefits in relation to different formulations and doses of inhaled ICS. Head-to-head comparisons are necessary to determine whether one combined inhaler is better than the others.
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Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Broncodilatadores/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Combinación de Medicamentos , Humanos , Nebulizadores y Vaporizadores , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Both long-acting beta(2)-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their co-administration in a combined inhaler is intended to facilitate adherence to medication regimens and to improve efficacy. Three preparations are currently available: fluticasone propionate/salmeterol (FPS). budesonide/formoterol (BDF) and mometasone furoate/formoterol (MF/F). OBJECTIVES: To assess the efficacy and safety of combined long-acting beta2-agonist and inhaled corticosteroid (LABA/ICS) preparations, as measured by clinical endpoints and pulmonary function testing, compared with inhaled corticosteroids (ICS) alone, in the treatment of adults with chronic obstructive pulmonary disease (COPD). SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials, which is compiled from systematic searches of multiple literature databases. The search was conducted in June 2013. In addition, we checked the reference lists of included studies and contacted the relevant manufacturers. SELECTION CRITERIA: Studies were included if they were randomised and double-blind. Compared studies combined LABA/ICS with the ICS component. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. The primary outcomes were exacerbations, mortality and pneumonia. Health-related quality of life (as measured by validated scales), lung function and side effects were secondary outcomes. Dichotomous data were analysed as fixed-effect odds ratios with 95% confidence intervals (CIs), and continuous data as mean differences or rate ratios and 95% CIs. MAIN RESULTS: A total of 15 studies of good methodological quality met the inclusion criteria by randomly assigning 7814 participants with predominantly poorly reversible, severe COPD. Data were most plentiful for the FPS combination. Exacerbation rates were significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94, 6 studies, N = 5601) compared with ICS alone. The mean exacerbation rate in the control (ICS) arms of the six included studies was 1.21 exacerbations per participant per year (range 0.88 to 1.60), and we would expect this to be reduced to a rate of 1.05 (95% CI 0.97 to 1.14) among those given combination therapy. Mortality was also lower with the combination (odds ratio (OR) 0.78, 95% CI 0.64 to 0.94, 12 studies, N = 7518) than with ICS alone, but this was heavily weighted by a three-year study of FPS. When this study was removed, no significant mortality difference was noted. The reduction in exacerbations did not translate into significantly reduced rates of hospitalisation due to COPD exacerbation (OR 0.93, 95% CI 0.80 to 1.07, 10 studies, N = 7060). Lung function data favoured combination treatment in the FPS, BDF and MF/F trials, but the improvement was small. Small improvements in health-related quality of life were measured on the St George's Respiratory Questionnaire (SGRQ) with FPS or BDF compared with ICS, but this was well below the minimum clinically important difference. Adverse event profiles were similar between the two treatments arms, and rates of pneumonia when it was diagnosed by chest x-ray (CXR) were lower than those reported in earlier trials. AUTHORS' CONCLUSIONS: Combination ICS and LABA offer some clinical benefits in COPD compared with ICS alone, especially for reduction in exacerbations. This review does not support the use of ICS alone when LABAs are available. Adverse events were not significantly different between treatments. Further long-term assessments using practical outcomes of current and new 24-hour LABAs will help determine their efficacy and safety. For robust comparisons as to their relative effects, long-term head-to-head comparisons are needed.