BACKGROUND: Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta₂-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta₂-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments.
OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid.
SEARCH METHODS: We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers' websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was 24 February 2021.
SELECTION CRITERIA: We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks' duration.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect.
MAIN RESULTS: Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229). In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol. In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence). Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation. The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence).
AUTHORS' CONCLUSIONS: Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome. We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.
BACKGROUND: Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about whether regular (daily) long-acting beta2-agonists (LABA) are safe when used in combination with inhaled corticosteroids (ICS). This updated Cochrane Review includes results from two large trials that recruited 23,422 adolescents and adults mandated by the US Food and Drug Administration (FDA).
OBJECTIVES: To assess the risk of mortality and non-fatal serious adverse events (SAEs) in trials that randomly assign participants with chronic asthma to regular formoterol and inhaled corticosteroids versus the same dose of inhaled corticosteroid alone.
SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data as well as FDA submissions in relation to formoterol. The date of the most recent search was February 2019.
SELECTION CRITERIA: We included randomised clinical trials (RCTs) with a parallel design involving adults, children, or both with asthma of any severity who received regular formoterol and ICS (separate or combined) treatment versus the same dose of ICS for at least 12 weeks.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors of the studies. We assessed our confidence in the evidence using GRADE recommendations. The primary outcomes were all-cause mortality and all-cause non-fatal serious adverse events.
MAIN RESULTS: We found 42 studies eligible for inclusion and included 39 studies in the analyses: 29 studies included 35,751 adults, and 10 studies included 4035 children and adolescents. Inhaled corticosteroids included beclomethasone (daily metered dosage 200 to 800 µg), budesonide (200 to 1600 µg), fluticasone (200 to 250 µg), and mometasone (200 to 800 µg). Formoterol metered dosage ranged from 12 to 48 µg daily. Fixed combination ICS was used in most of the studies. We judged the risk of selection bias, performance bias, and attrition bias as low, however most studies did not report independent assessment of causation of SAEs.DeathsSeventeen of 18,645 adults taking formoterol and ICS and 13 of 17,106 adults taking regular ICS died of any cause. The pooled Peto odds ratio (OR) was 1.25 (95% confidence interval (CI) 0.61 to 2.56, moderate-certainty evidence), which equated to one death occurring for every 1000 adults treated with ICS alone for 26 weeks; the corresponding risk amongst adults taking formoterol and ICS was also one death (95% CI 0 to 2 deaths). No deaths were reported in the trials on children and adolescents (4035 participants) (low-certainty evidence).In terms of asthma-related deaths, no children and adolescents died from asthma, but three of 12,777 adults in the formoterol and ICS treatment group died of asthma (both low-certainty evidence).Non-fatal serious adverse eventsA total of 401 adults experienced a non-fatal SAE of any cause on formoterol with ICS, compared to 369 adults who received regular ICS. The pooled Peto OR was 1.00 (95% CI 0.87 to 1.16, high-certainty evidence, 29 studies, 35,751 adults). For every 1000 adults treated with ICS alone for 26 weeks, 22 adults had an SAE; the corresponding risk for those on formoterol and ICS was also 22 adults (95% CI 19 to 25).Thirty of 2491 children and adolescents experienced an SAE of any cause when receiving formoterol with ICS, compared to 13 of 1544 children and adolescents receiving ICS alone. The pooled Peto OR was 1.33 (95% CI 0.71 to 2.49, moderate-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 8 had an non-fatal SAE; the corresponding risk amongst those on formoterol and ICS was 11 children and adolescents (95% CI 6 to 21).Asthma-related serious adverse eventsNinety adults experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 102 with ICS alone. The pooled Peto OR was 0.86 (95% CI 0.64 to 1.14, moderate-certainty evidence, 28 studies, 35,158 adults). For every 1000 adults treated with ICS alone for 26 weeks, 6 adults had an asthma-related non-fatal SAE; the corresponding risk for those on formoterol and ICS was 5 adults (95% CI 4 to 7).Amongst children and adolescents, 9 experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 5 on ICS alone. The pooled Peto OR was 1.18 (95% CI 0.40 to 3.51, very low-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 3 had an asthma-related non-fatal SAE; the corresponding risk on formoterol and ICS was 4 (95% CI 1 to 11).
AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death (all-cause or asthma-related) in adults taking combined formoterol and ICS versus ICS alone (moderate- to low-certainty evidence). No deaths were reported in children and adolescents. The risk of dying when taking either treatment was very low, but we cannot be certain if there is a difference in mortality when taking additional formoterol to ICS (low-certainty evidence).We did not find a difference in the risk of non-fatal SAEs of any cause in adults (high-certainty evidence). A previous version of the review had shown a lower risk of asthma-related SAEs in adults taking combined formoterol and ICS; however, inclusion of new studies no longer shows a difference between treatments (moderate-certainty evidence).The reported number of children and adolescents with SAEs was small, so uncertainty remains in this age group.We included results from large studies mandated by the FDA. Clinical decisions and information provided to patients regarding regular use of formoterol and ICS need to take into account the balance between known symptomatic benefits of formoterol and ICS versus the remaining degree of uncertainty associated with its potential harmful effects.
BACKGROUND: Epidemiological evidence has suggested a link between use of beta₂-agonists and increased asthma mortality. Much debate has surrounded possible causal links for this association, and whether regular (daily) long-acting beta₂-agonists (LABAs) are safe, particularly when used in combination with inhaled corticosteroids (ICSs). This is an update of a Cochrane Review that now includes data from two large trials including 11,679 adults and 6208 children; both were mandated by the US Food and Drug Administration (FDA). OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events (SAEs) in trials that randomised participants with chronic asthma to regular salmeterol and ICS versus the same dose of ICS.
SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trials registers for unpublished trial data. We also checked FDA submissions in relation to salmeterol. The date of the most recent search was 10 October 2018.
SELECTION CRITERIA: We included parallel-design randomised trials involving adults, children, or both with asthma of any severity who were randomised to treatment with regular salmeterol and ICS (in separate or combined inhalers) versus the same dose of ICS of at least 12 weeks in duration.
DATA COLLECTION AND ANALYSIS: We conducted the review according to standard procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors, from ClinicalTrials.gov, and from FDA submissions. We assessed our confidence in the evidence according to current GRADE recommendations.
MAIN RESULTS: We have included in this review 41 studies (27,951 participants) in adults and adolescents, along with eight studies (8453 participants) in children. We judged that the overall risk of bias was low for all-cause events, and we obtained data on SAEs from all study authors. All except 542 adults (and none of the children) were given salmeterol and fluticasone in the same (combination) inhaler.DeathsEleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 taking regular ICS at the same dose. The pooled Peto odds ratio (OR) was 0.80 (95% confidence interval (CI) 0.36 to 1.78; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). In other words, for every 1000 adults treated for 25 weeks, one death occurred among those on ICS alone, and the corresponding risk among those taking salmeterol and ICS was also one death (95% CI 0 to 2 deaths).No children died, and no adults or children died of asthma, so we remain uncertain about mortality in children and about asthma mortality in any age group.Non-fatal serious adverse eventsA total of 332 adults receiving regular salmeterol with ICS experienced a non-fatal SAE of any cause, compared to 282 adults receiving regular ICS. The pooled Peto OR was 1.14 (95% CI 0.97 to 1.33; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). For every 1000 adults treated for 25 weeks, 21 adults on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 23 adults (95% CI 20 to 27).Sixty-five of 4229 children given regular salmeterol with ICS suffered an SAE of any cause, compared to 62 of 4224 children given regular ICS. The pooled Peto OR was 1.04 (95% CI 0.73 to 1.48; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, 15 children on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 15 children (95% CI 11 to 22).Asthma-related serious adverse eventsEighty and 67 adults in each group, respectively, experienced an asthma-related non-fatal SAE. The pooled Peto OR was 1.15 (95% CI 0.83 to 1.59; participants = 27,951; studies = 41; I² = 0%; low-certainty evidence). For every 1000 adults treated for 25 weeks, five receiving ICS alone had an asthma-related SAE, and the corresponding risk among those on salmeterol and ICS was six adults (95% CI 4 to 8).Twenty-nine children taking salmeterol and ICS and 23 children taking ICS alone reported asthma-related events. The pooled Peto OR was 1.25 (95% CI 0.72 to 2.16; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, five receiving an ICS alone had an asthma-related SAE, and the corresponding risk among those receiving salmeterol and ICS was seven children (95% CI 4 to 12).
AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death or serious adverse events in either adults or children. However, trial authors reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. Therefore, the risk of dying from asthma on either treatment was very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS.Inclusion of new trials has increased the precision of the estimates for non-fatal SAEs of any cause. We can now say that the worst-case estimate is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to treatment with ICS alone). These possible risks still have to be weighed against the benefits experienced by people who take combination treatment.However more than 90% of prescribed treatment was taken in the new trials, so the effects observed may be different from those seen with salmeterol in combination with ICS in daily practice.
ANTECEDENTES: La evidencia epidemiológica ha sugerido una relación entre los agonistas beta2 y el aumento de la mortalidad por asma. Se ha debatido mucho sobre las posibles relaciones causales de esta asociación, y si regularmente (a diario) de acción prolongada beta2-agonistas son seguros.
OBJETIVOS: El objetivo de esta revisión es evaluar el riesgo de mortales y no mortales eventos adversos graves en los ensayos con asignación al azar que los pacientes con asma crónica a formoterol regular versus placebo o regulares de corta duración beta2-agonistas.
MÉTODOS DE BÚSQUEDA: Los ensayos se identificaron mediante el Registro del Grupo Cochrane de Vías Respiratorias de ensayos especializados. Se verificaron las páginas web de los registros de ensayos clínicos para los datos de ensayos no publicados y la Food and Drug Administration (FDA) propuestas en relación con el formoterol. La fecha de la búsqueda más reciente fue en enero de 2012.
CRITERIOS DE SELECCIÓN: Se incluyeron los ensayos controlados, de diseño paralelo clínicos en pacientes de cualquier edad y gravedad del asma, si los pacientes aleatorizados al tratamiento con formoterol de forma habitual y eran de una duración mínima de 12 semanas. El uso concomitante de corticoides inhalados se le permitió, siempre y cuando esto no era parte del régimen de tratamiento al azar.
RECOPILACIÓN Y ANÁLISIS DE DATOS: Dos revisores de forma independiente, seleccionaron los ensayos para su inclusión en la revisión. Un autor extrajo los datos de resultados y el segundo autor los verificó. Se buscaron los datos publicados sobre la mortalidad y los eventos adversos graves.
RESULTADOS PRINCIPALES: La revisión incluye 22 estudios (8032 participantes) compararon el formoterol regulares con el placebo y el salbutamol. No fatales de datos de eventos adversos graves se podría obtener para todos los participantes de los estudios publicados que comparan el formoterol y placebo, pero sólo el 80% de aquellos que compararon el formoterol con salbutamol o terbutalina.
Tres muertes ocurrieron en el uso habitual de formoterol y ninguno en el grupo placebo, esta diferencia no fue estadísticamente significativa. No fue posible evaluar la mortalidad específica de la vista del pequeño número de muertes. No fatales acontecimientos adversos graves aumentaron de manera significativa al uso habitual de formoterol se comparó con placebo (odds ratio (OR) 1,57, IC 95%: 1,06 a 2,31). Un extra de evento adverso grave se produjo durante 16 semanas por cada 149 personas tratadas con formoterol de forma habitual (95% IC 66 a 1407 personas). El aumento fue mayor en niños que en adultos, pero el impacto de la edad no fue estadísticamente significativa. Los datos presentados a la FDA indican que el aumento de los relacionados con el asma eventos adversos graves sigue siendo importante en los pacientes que toman formoterol de forma habitual, que también estuvieron presentes los corticosteroides inhalados.
No hay un aumento significativo en mortales o no-acontecimientos adversos graves se encontró al uso habitual de formoterol se comparó con el ordinario de salbutamol o terbutalina.
CONCLUSIONES DE LOS REVISORES: En comparación con el placebo, hemos encontrado un mayor riesgo de efectos adversos graves con formoterol de forma habitual, y esto no parece ser abolida en pacientes que toman corticoides inhalados. El efecto sobre los eventos adversos graves de formoterol de forma habitual en los niños fue mayor que el efecto en los adultos, pero la diferencia entre los grupos de edad no fue significativa.
Los datos sobre todas las causas eventos adversos graves se informó con más detalle en artículos de revistas, y no se combina con todos los tipos de gravedad de los efectos adversos o limitados a aquellos acontecimientos que son pensados por el investigador como relacionados con las drogas.
ANTECEDENTES: En revisiones Cochrane anteriores se ha demostrado un aumento de efectos adversos graves con el uso de formoterol y salmeterol regular en asma crónica.
OBJETIVOS: Nos propusimos comparar los riesgos de mortalidad y eventos adversos graves no fatales en los ensayos clínicos que incluyen pacientes con asma crónica aleatorizados a formoterol de forma habitual versus al tratamiento habitual con salmeterol.
MÉTODOS DE BÚSQUEDA: Los ensayos se identificaron mediante el Registro Especializado de Ensayos Clínicos del Grupo Cochrane de Vías Respiratorias. Se revisaron los sitios web de registros de ensayos clínicos de los fabricantes en busca de datos de ensayos no publicados, y también se revisaron las presentaciones a la Administración de Alimentos y Drogas (US Food and Drug Administration, FDA) en relación a formoterol y salmeterol. La fecha de búsqueda más reciente fue enero de 2012.
CRITERIOS DE SELECCIÓN: Se incluyeron ensayos clínicos controlados, con diseño paralelo, en pacientes de cualquier edad y con cualquier gravedad de asma que hubieran aleatorizado a los pacientes a tratamiento regular con formoterol versus tratamiento regular con salmeterol (sin aleatorización a corticoides inhalatorios), que tuviesen al menos 12 semanas de duración.
OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos revisores en forma independiente seleccionaron los ensayos para la inclusión en la revisión y extrajeron los datos de los resultados. Se solicitaron datos no publicados sobre mortalidad y eventos adversos graves a los patrocinadores y los autores.
RESULTADOS PRINCIPALES: La revisión incluyó cuatro estudios (que incluyen 1.116 adultos y 156 niños). Todos los estudios fueron abiertos y reclutaron pacientes que ya estaban utilizando corticoides inhalados para el asma, y todos los estudios aportaron datos sobre eventos adversos serios. Todos los estudios compararon formoterol 12 μg frente a salmeterol 50 μg dos veces al día. En adultos, todos los estudios comparaban Foradil Aerolizer contra Serevent Diskus, y el estudio en niños comparó Oxis Turbuhaler contra Serevent Accuhaler. Hubo sólo una muerte en un adulto (no relacionada con el asma) y ninguna en niños, y no hubo diferencias significativas en eventos adversos graves no fatales comparando formoterol con salmeterol en adultos (odds ratio de Peto (OR) 0,77, intervalo de confianza del 95% (IC) 0,46 a 1,28), o niños (OR de Peto 0,95, IC 95% 0,06 a 15,33). Durante un período de seis meses, en los estudios en adultos que contribuyeron a este análisis, los porcentajes de eventos adversos graves fueron 5,1% para formoterol y 6,4% para salmeterol; y durante un período de tres meses los porcentajes de eventos adversos graves en niños fueron 1,3% para formoterol y 1,3% para salmeterol.
CONCLUSIONES DE LOS AUTORES: Se identificaron cuatro estudios que compararon formoterol regular contra salmeterol regular (sin aleatorización a corticoides inhalados, pero todos los participantes utilizaban de base corticoides inhalados en forma regular). Los eventos fueron poco frecuentes, y por consiguiente, muy pocos pacientes han sido estudiados para permitir que se elabore cualquier conclusión sobre la seguridad relativa de formoterol y salmeterol. Los eventos adversos graves relacionados al asma fueron poco frecuentes y no se reportaron muertes relacionadas con asma.
ANTECEDENTES: Los datos epidemiológicos han sugerido una relación entre el uso de agonistas beta2 y el aumento de la mortalidad por asma. Se ha debatido mucho sobre las posibles relaciones causales de esta asociación, y si regulares (diarios) de acción prolongada beta2-agonistas son seguros.
OBJETIVOS: El objetivo de esta revisión es evaluar el riesgo de mortales y no mortales eventos adversos graves en los ensayos aleatorios de que los pacientes con asma crónica al tratamiento habitual con salmeterol versus placebo o regulares de corta duración beta2-agonistas.
ESTRATEGIA DE BÚSQUEDA: Los ensayos se identificaron mediante el Registro del Grupo Cochrane de Vías Respiratorias Especializado de Ensayos. Se verificaron los sitios web de registros de ensayos clínicos para los datos de ensayos no publicados y presentados a la FDA en relación con salmeterol. La fecha de la búsqueda más reciente fue en agosto de 2011.
CRITERIOS DE SELECCIÓN: Se incluyeron los ensayos controlados paralelos diseño clínicos en pacientes de cualquier edad y gravedad del asma, si los pacientes asignados al azar al tratamiento con salmeterol regular y eran de una duración mínima de 12 semanas. El uso concomitante de corticoides inhalados fue permitido, siempre y cuando esto no era parte del régimen de tratamiento aleatorizado.
RECOPILACIÓN Y ANÁLISIS DE DATOS: Dos revisores de forma independiente seleccionaron los ensayos para su inclusión en la revisión. Un autor extrajo los datos de los resultados y el segundo los verificó. Se buscaron datos no publicados sobre mortalidad y eventos adversos graves.
RESULTADOS PRINCIPALES: La revisión incluye 26 ensayos que compararon el salmeterol con placebo y ocho ensayos que compararon con salbutamol. Estos incluyeron 62.815 participantes con asma (incluidos 2.599 niños). En seis ensayos (2766 pacientes), no hay datos de eventos adversos graves se podía obtener.
Todas las causas de mortalidad fue más alta con tratamiento habitual con salmeterol que con placebo, pero el aumento no fue significativo (odds ratio (OR) 1,33 (IC del 95%: 0,85 a 2,08)). No fatales acontecimientos adversos graves fueron significativamente mayores con tratamiento habitual con salmeterol se comparó con placebo (OR 1.15 IC del 95%: 1,02 a 1,29). Un evento adverso grave adicional se produjeron más de 28 semanas para cada 188 personas tratadas con tratamiento habitual con salmeterol (95% CI 95-2606). No hay pruebas suficientes para evaluar si el riesgo en los niños es mayor o menor que en los adultos. No se encontró un aumento significativo en mortales o no mortales eventos adversos graves cuando se comparó el tratamiento habitual con salmeterol con tratamiento habitual con salbutamol.
Se combinaron los datos de los pacientes individuales a partir de los dos grandes estudios (SNS: n = 25.180 y SMART: n = 26.355), ya que todas las muertes relacionadas con el asma en adultos se produjo en estos estudios. En los pacientes que no estaban tomando corticosteroides inhalados, en comparación con el salbutamol regular o placebo, hubo un aumento significativo en el riesgo de muerte por asma con tratamiento habitual con salmeterol (OR DE PETO: 6,15 IC 95%: 1,73 a 21,84). El intervalo de confianza para los pacientes que estaban tomando los corticosteroides inhalados es generalizado y no puede gobernar dentro o fuera de un aumento de la mortalidad por asma en presencia de un corticosteroide inhalado (Peto OR 2,03 IC del 95%: 0,82 a 5,00).
CONCLUSIONES DE LOS REVISORES: En comparación con placebo, se ha encontrado un mayor riesgo de eventos adversos graves con salmeterol regular. También hay un claro aumento en el riesgo de mortalidad relacionada con el asma en pacientes que no utilizan corticosteroides inhalados en los dos estudios de vigilancia de gran tamaño. Aunque el aumento de la mortalidad relacionada con el asma fue menor en los pacientes que toman corticosteroides inhalados al inicio del estudio, el intervalo de confianza es amplio, por lo que no se puede concluir que los corticosteroides inhalados suprimir los riesgos de salmeterol regular. Los efectos adversos del tratamiento habitual con salmeterol en niños siguen siendo inciertas debido al pequeño número de niños estudiados.
Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta₂-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta₂-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments.
OBJECTIVES:
To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid.
SEARCH METHODS:
We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers' websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was 24 February 2021.
SELECTION CRITERIA:
We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks' duration.
DATA COLLECTION AND ANALYSIS:
Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect.
MAIN RESULTS:
Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229). In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol. In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence). Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation. The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence).
AUTHORS' CONCLUSIONS:
Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome. We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.
