Tratamiento habitual con formoterol y un corticosteroide inhalado versus tratamiento habitual con salmeterol y un corticosteroide inhalado para el asma crónica: eventos adversos graves
Resumen
Antecedentes
El asma se caracteriza por la inflamación crónica de las vías respiratorias y por exacerbaciones recurrentes que incluyen sibilancias, opresión torácica y tos. El tratamiento con corticosteroides y broncodilatadores inhalados puede dar lugar a un control efectivo de los síntomas, a la prevención de morbilidad adicional y a una mejoría en la calidad de vida. Sin embargo, en revisiones Cochrane anteriores se ha mostrado un aumento de los eventos adversos graves con el uso de formoterol habitual y de salmeterol habitual (agonistas beta₂ de acción prolongada) en comparación con placebo para el asma crónica. Este aumento fue estadísticamente significativo en los ensayos que no asignaron al azar a los participantes a un corticosteroide inhalado, pero no lo fue cuando el formoterol o el salmeterol se combinaron con un corticosteroide inhalado. Se determinó que los intervalos de confianza eran demasiado amplios para asegurar que el agregado de un corticosteroide inhalado haga que los agonistas beta₂ de acción prolongada habituales sean completamente seguros; los escasos participantes y eventos adversos graves en estos ensayos impiden establecer una decisión definitiva acerca de la seguridad de los tratamientos combinados.
Objetivos
Evaluar los riesgos de mortalidad y de eventos adversos graves no mortales en ensayos que asignaron al azar a pacientes con asma crónica a tratamiento habitual con formoterol y un corticosteroide inhalado en comparación con el tratamiento habitual con salmeterol y un corticosteroide inhalado.
Métodos de búsqueda
Para identificar informes de ensayos aleatorizados para inclusión en esta revisión se realizaron búsquedas en el Registro de ensayos del Grupo Cochrane de Vías respiratorias (Cochrane Airways Group), en CENTRAL, MEDLINE, Embase y en dos registros de ensayos. Se revisaron los sitios web de los fabricantes y registros de ensayos clínicos para buscar datos de ensayos no publicados y también se examinaron solicitudes presentadas a la Food and Drug Administration (FDA) relacionadas con el formoterol y el salmeterol. La fecha de búsqueda más reciente fue el 24 de febrero de 2021.
Criterios de selección
Se incluyeron los ensayos clínicos controlados con un diseño paralelo que reclutaron a pacientes de cualquier edad y gravedad del asma, si asignaron al azar a los pacientes a tratamiento con formoterol habitual versus salmeterol habitual (cada uno con un corticosteroide inhalado asignado al azar) y tenían una duración mínima de 12 semanas.
Obtención y análisis de los datos
Dos autores de la revisión, de forma independiente, seleccionaron los ensayos para inclusión en la revisión y extrajeron los datos de los desenlaces de artículos publicados y registros de ensayos, además aplicaron la calificación de GRADE a los resultados. Se solicitaron los datos no publicados sobre la mortalidad y los eventos adversos graves a los patrocinadores y a los autores de los estudios. Los desenlaces principales fueron la mortalidad por todas las causas y los eventos adversos graves no mortales. Se optó por no calcular un resultado promedio de todas las formulaciones de formoterol y corticosteroides inhalados, ya que las dosis y los dispositivos de administración son demasiado diversos para asumir un efecto de clase único.
Resultados principales
Veintiún estudios con 11 572 adultos y adolescentes y dos estudios con 723 niños cumplieron los criterios de elegibilidad de la revisión. No hubo datos disponibles de dos estudios; por lo que no se incluyeron en el análisis. Entre los estudios de adultos y adolescentes, siete compararon formoterol y budesonida con salmeterol y fluticasona (n = 7764), seis compararon formoterol y beclometasona con salmeterol y fluticasona (n = 1923), dos compararon formoterol y mometasona con salmeterol y fluticasona (n = 1126), dos compararon formoterol y fluticasona con salmeterol y fluticasona (n = 790) y uno comparó formoterol y budesonida con salmeterol y budesonida (n = 229).
En total se registraron cinco muertes entre adultos y se consideró que ninguna estaba relacionada con el asma. La certeza de la evidencia para la mortalidad por todas las causas fue baja, ya que no hubo suficientes muertes para poder establecer conclusiones precisas con respecto al riesgo de mortalidad con la combinación de formoterol versus la combinación de salmeterol.
En total, 201 adultos notificaron eventos adversos graves no mortales. En los estudios que compararon el formoterol y la budesonida con el salmeterol y la fluticasona, hubo 77 en el grupo de formoterol y 68 en el grupo de salmeterol (odds ratio [OR] de Peto 1,14; intervalo de confianza [IC] del 95%: 0,82 a 1,59; 5935 participantes, siete estudios; evidencia de certeza moderada). En los estudios que compararon el formoterol y la budesonida, 12 adultos presentaron eventos en el grupo de formoterol y 13 en el de salmeterol (OR de Peto 0,94; IC del 95%: 0,43 a 2,08; 1941 participantes, seis estudios; evidencia de certeza moderada). En los estudios que compararon el formoterol y la mometasona, hubo 18 en el grupo de formoterol y 11 en el de salmeterol (OR de Peto 1,02; IC del 95%: 0,47 a 2,20; 1126 participantes, dos estudios; evidencia de certeza moderada). Un adulto del grupo de salmeterol en los estudios de formoterol y fluticasona presentó un evento (OR de Peto 0,05; IC del 95%: 0,00 a 3,10; 293 participantes, dos estudios; evidencia de certeza baja). Otro adulto del grupo de formoterol en el estudio de formoterol y budesonida versus salmeterol y budesonida presentó un evento (OR de Peto 7,45; IC del 95%: 0,15 a 375,68; 229 participantes, un estudio; evidencia de certeza baja).
Solo 46 adultos notificaron haber presentado eventos adversos graves relacionados con el asma. La certeza de la evidencia fue baja a muy baja, debido al escaso número de eventos y a la ausencia de una evaluación independiente de causalidad.
Los dos estudios realizados en niños compararon formoterol y fluticasona con salmeterol y fluticasona. No se informaron muertes ni eventos adversos graves relacionados con el asma en estos estudios. Se informaron cuatro eventos adversos graves por todas las causas: tres en el grupo de formoterol y uno en el de salmeterol (OR de Peto 2,72; IC del 95%: 0,38 a 19,46; 548 participantes, dos estudios; evidencia de certeza baja).
Conclusiones de los autores
En general, en adultos y en niños, no hay evidencia suficiente para mostrar si el formoterol habitual en combinación con la budesonida, la beclometasona, la fluticasona o la mometasona tiene un perfil de seguridad diferente al del salmeterol en combinación con la fluticasona o la budesonida. Se informaron cinco muertes por cualquier causa en todos los estudios y ninguna muerte por asma; esta información no es suficiente para establecer una conclusión firme acerca de los riesgos relativos de mortalidad con los inhaladores combinados de formoterol en comparación con los inhaladores combinados de salmeterol. La evidencia sobre los eventos adversos graves no mortales por todas las causas indica que probablemente haya poca o ninguna diferencia entre los inhaladores de formoterol/budesonida y los de salmeterol/fluticasona. Sin embargo, los eventos con los otros inhaladores combinados de formoterol fueron demasiado escasos para poder establecer conclusiones. Solo se consideró que 46 eventos adversos graves no mortales estuvieron relacionados con el asma; esta baja cifra junto con la ausencia de una evaluación independiente de los desenlaces, implica que existe una confianza muy baja en este desenlace.
No se encontró evidencia de problemas de seguridad que afectaran la elección entre los inhaladores combinados de salmeterol y de formoterol utilizados para el tratamiento de mantenimiento habitual en adultos y niños con asma.
PICO
Resumen en términos sencillos
¿Presentan las personas con asma menos episodios adversos graves cuando reciben formoterol y corticosteroides inhalados en comparación con salmeterol y corticosteroides inhalados?
Antecedentes
El asma es una enfermedad que afecta a las vías respiratorias, es decir, a los pequeños conductos que transportan el aire hacia el interior y el exterior de los pulmones. Cuando una persona con asma entra en contacto con un desencadenante del asma, las vías respiratorias se irritan y los músculos que rodean las paredes de las vías respiratorias se tensan, de modo que éstas se estrechan (broncoconstricción) y el revestimiento de las vías respiratorias se inflama y comienza a inflamarse. A veces, se acumula una mucosidad pegajosa o flema, que puede estrechar aún más las vías respiratorias. Estas reacciones hacen que las vías respiratorias se estrechen e irriten, dificultando la respiración y provocando tos, silbidos, dificultad para respirar y opresión en el pecho. Por lo general, a las personas con asma se les recomienda utilizar corticosteroides inhalados para combatir la inflamación subyacente, pero si el asma aún no está controlada, las guías clínicas actuales para las personas con asma recomiendan la introducción de un medicamento adicional para ayudar. Una estrategia habitual en estas situaciones es utilizar un agonista beta de acción prolongada: formoterol o salmeterol. Un agonista beta de acción prolongada es un fármaco inhalado que abre las vías respiratorias (broncodilatador) y facilita la respiración. Los corticosteroides inhalados se pueden agregar a estos broncodilatadores en el mismo inhalador. Diversos corticosteroides inhalados se utilizan en inhaladores combinados con formoterol o salmeterol.
A partir de revisiones Cochrane anteriores se sabe que hay un pequeño aumento de los episodios adversos graves (como crisis de asma muy graves y otros episodios potencialmente mortales) cuando se administra formoterol habitual o salmeterol habitual sin corticosteroides inhalados, pero este aumento no se observó al utilizar estos medicamentos con un corticosteroide inhalado en un solo inhalador combinado. Esta revisión buscó información de los ensayos que compararon los dos tratamientos (es decir, en los que las personas que recibían salmeterol con un corticosteroide inhalado se compararon directamente con las personas que recibían formoterol y un corticosteroide inhalado) para ver si se podía determinar qué medicamento era el más seguro.
Características de los estudios
Se realizó una búsqueda de estudios en febrero de 2021. En esta revisión se incluyeron 23 ensayos controlados aleatorizados que compararon formoterol y corticosteroides inhalados con salmeterol y corticosteroides inhalados. Veintiún estudios con 11 572 participantes incluyeron adultos y adolescentes. La edad inferior en estos 21 estudios varió entre los 12 y los 16 o 18 años. Ocho de estos estudios (7730 adultos) compararon los inhaladores combinados de formoterol/budesonida con salmeterol/fluticasona, y un número menor (1472, 1126 y 1075 adultos) compararon las otras combinaciones de formoterol con salmeterol/fluticasona. Solo hubo 229 adultos en los estudios que compararon formoterol/budesonida con salmeterol/budesonida. Dos estudios de 723 participantes incluyeron a niños; los intervalos de edad en estos estudios fueron de cuatro a 12 y de cinco a 12 años; ambos compararon inhaladores de formoterol/fluticasona con inhaladores de salmeterol/fluticasona.
Resultados clave
No fue posible detectar diferencias claras entre la combinación formoterol/corticoides inhalados y salmeterol/corticoides inhalados en la mortalidad por todas las causas ni en los episodios adversos no mortales por cualquier causa relacionados con el asma. No se informaron muertes por asma. Los estudios incluidos tenían suficientes participantes para evaluar los efectos beneficiosos del tratamiento, pero no incluían a suficientes personas para determinar la seguridad comparativa de estos tratamientos.
Calidad de la evidencia
En general, los estudios incluidos tuvieron bajos niveles de sesgo, pero hubo una baja incidencia de mortalidad y episodios adversos graves, lo que redujo la certeza de las evidencia para diferentes desenlaces. La calidad de la evidencia para la mortalidad por todas las causas y los episodios adversos graves no mortales por todas las causas se consideró baja y moderada, respectivamente. La calidad de la evidencia para los episodios adversos graves relacionados con el asma fue baja a muy baja, debido al escaso número de episodios relacionados con el asma y a la falta de una evaluación independiente de causalidad de los episodios.
Conclusiones
No se encontraron problemas de seguridad que afectaran la elección entre los inhaladores combinados de salmeterol y de formoterol utilizados para el tratamiento de mantenimiento habitual en adultos y niños con asma.
Authors' conclusions
Summary of findings
| Adults formoterol/ICS compared to salmeterol/ICS for chronic asthma: all‐cause mortality | ||||||
| Patient or population: adults, chronic asthma: all‐cause mortality | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | №. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with salmeterol/ICS | Risk with formoterol/ICS | |||||
| All‐cause mortality ‐ formoterol/budesonide vs salmeterol/fluticasone | 34 per 100,000 | 35 per 100,000 | OR 1.03 | 5935 | ⊕⊕⊝⊝ | |
| All‐cause mortality ‐ formoterol/beclomethasone vs salmeterol/fluticasone | No deaths | ‐ | 1257 | N/A | ||
| All‐cause mortality ‐ formoterol/mometasone vs salmeterol/fluticasone | 0 per 100,000 | 0 per 100,000 | OR 4.46 | 1126 | ⊕⊕⊝⊝ | Zero events on salmeterol prevents calculation of absolute risk |
| All‐cause mortality ‐ formoterol/fluticasone vs salmeterol/fluticasone | 0 per 100,000 | 0 per 100,000 | OR 7.39 | 270 | ⊕⊕⊝⊝ | Zero events on salmeterol prevents calculation of absolute risk |
| All‐cause mortality formoterol/budesonide vs salmeterol/budesonide Follow‐up: mean 12 weeks | No deaths | ‐ | 229 (1 RCT) | N/A | ||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aVery wide confidence interval, downgraded by 2 points. | ||||||
| Adults: formoterol/ICS compared to salmeterol/ICS for chronic asthma: all‐cause serious adverse events | ||||||
| Patient or population: adults, chronic asthma: serious adverse events | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | №. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with salmeterol/ICS | Risk with formoterol/ICS | |||||
| All‐cause non‐fatal serious adverse events ‐ formoterol/budesonide vs salmeterol/fluticasone | 2290 per 100,000 | 2603 per 100,000 | OR 1.14 | 5935 | ⊕⊕⊕⊝ | |
| All‐cause non‐fatal serious adverse events ‐ formoterol/beclomethasone vs salmeterol/fluticasone | 1325 per 100,000 | 1247 per 100,000 | OR 0.94 | 1941 | ⊕⊕⊕⊝ | |
| All‐cause non‐fatal serious adverse events ‐ formoterol/mometasone vs salmeterol/fluticasone | 2273 per 100,000 | 2317 per 100,000 | OR 1.02 | 1126 | ⊕⊕⊕⊝ | |
| All‐cause non‐fatal serious adverse events ‐ formoterol/fluticasone vs salmeterol/fluticasone | 935 per 100,000 | 47 per 100,000 | OR 0.05 | 293 | ⊕⊕⊝⊝ | |
| All‐cause non‐fatal serious adverse events ‐ formoterol/budesonide vs salmeterol/budesonide | 0 per 100,000 | 0 per 100,000 | OR 7.45 | 229 | ⊕⊕⊝⊝ | Zero events on salmeterol prevents calculation of absolute risk |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aConfidence interval wide, downgraded by 1 point. bConfidence interval very wide, downgraded by 2 points. | ||||||
| Adults: formoterol/ICS compared to salmeterol/ICS for chronic asthma: asthma‐related serious adverse events | ||||||
| Patient or population: adults, chronic asthma: asthma‐related serious adverse events | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | №. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with salmeterol/ICS | Risk with formoterol/ICS | |||||
| Asthma‐related non‐fatal serious adverse events ‐ formoterol/budesonide vs salmeterol/fluticasone | 842 per 100,000 | 583 per 100,000 | OR 0.69 | 5935 | ⊕⊕⊝⊝ | |
| Asthma‐related non‐fatal serious adverse events ‐ formoterol/beclomethasone vs salmeterol/fluticasone | 131 per 100,000 | 132 per 100,000 | OR 1.01 | 1510 | ⊕⊝⊝⊝ | |
| Asthma related non‐fatal serious adverse events ‐ formoterol/mometasone v's salmeterol/fluticasone | 0 per 100,000 | 0 per 100,000 | OR 7.00 | 722 | ⊕⊝⊝⊝ | Zero events on salmeterol prevents calculation of absolute risk |
| Asthma‐related non‐fatal serious adverse events ‐ formoterol/fluticasone vs salmeterol/fluticasone | 935 per 100,000 | 47 per 100,000 | OR 0.05 | 293 | ⊕⊕⊝⊝ | |
| Asthma‐related non‐fatal serious adverse events ‐ formoterol/budesonide vs salmeterol/budesonide | 0 per 100,000 | 0 per 100,000 | Not estimable | 229 | N/A | No events |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aConfidence interval wide, downgraded by 1 point. bNo independent assessment of causation, downgraded by 1 point. cConfidence interval very wide, downgraded by 2 points. | ||||||
| Children: formoterol/fluticasone compared to salmeterol/fluticasone for chronic asthma: serious adverse events | ||||||
| Patient or population: children, chronic asthma: serious adverse events | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | №. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with salmeterol/fluticasone | Risk with formoterol/fluticasone | |||||
| All‐cause mortality | No deaths
| ‐ | 548 | N/A | ||
| All‐cause non‐fatal serious adverse events | 365 per 100,000 | 987 per 100,000 | OR 2.72 | 548 | ⊕⊕⊝⊝ | |
| Asthma‐related non‐fatal serious adverse events | No asthma‐related events | ‐ | 548 | N/A | ||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aVery wide confidence interval, downgraded by 2 points. | ||||||
Background
Description of the condition
When asthma is not controlled by low‐dose inhaled corticosteroids alone, many asthma guidelines recommend additional long‐acting beta₂‐agonists. Several Cochrane Reviews have addressed the efficacy of long‐acting beta₂‐agonists given with inhaled corticosteroids (Ni Chroinin 2009; Ni Chroinin 2010), in comparison with placebo (Walters 2007), short‐acting beta₂‐agonists (Walters 2002), leukotriene‐receptor antagonists (Ducharme 2011), and increased doses of inhaled corticosteroids (Ducharme 2010). The beneficial effects of long‐acting beta₂‐agonists on lung function, symptoms, quality of life, and exacerbations requiring oral steroids have been demonstrated, and a rationale has been put forward for their use in combination with an inhaled corticosteroid (Barnes 2002).
However, a meta‐analysis of the effects of long‐acting beta₂‐agonists on severe asthma exacerbations and asthma‐related deaths concluded that "long‐acting beta‐agonists have been shown to increase severe and life‐threatening asthma exacerbations, as well as asthma‐related deaths" (Salpeter 2006). These review authors considered trials that compared any long‐acting beta₂‐agonists with placebo and were not able to include 28 trials in the primary analysis (including nearly 6000 patients) because information on asthma‐related deaths was not provided.
Description of the intervention
Currently, two long‐acting beta₂‐agonists are available for treatment of asthma: formoterol (also known as eformoterol) and salmeterol. These two drugs, which are known to have differences in speed of onset and receptor activity, are used in different ways (e.g. salmeterol has slower onset of action than formoterol; Lotvall 2001). For this reason, we have considered salmeterol and formoterol separately in our previous work. Formoterol is now available in combination inhalers with budesonide, beclomethasone, mometasone, or fluticasone, and salmeterol is available in combination with fluticasone or budesonide.
How the intervention might work
In spite of the benefits noted in people with asthma, concern remains that regular treatment with long‐acting beta₂‐agonists might lead to an increase in asthma‐related deaths (as seen in SMART 2006). Regular treatment with beta₂‐agonists can lead to tolerance to their bronchodilator effects with both long‐acting and short‐acting compounds (Lipworth 1997); the pharmacology of beta₂‐agonists is detailed in Appendix 1. A number of molecular mechanisms have been proposed to explain the possible detrimental effects of long‐term beta₂‐agonist use in asthma, including receptor down‐regulation and desensitisation (Giembycz 2006), as outlined in detail in Appendix 2.
Why it is important to do this review
Two of our published reviews have assessed the risks of fatal and non‐fatal serious adverse events with regular salmeterol and formoterol compared to placebo or short‐acting beta₂‐agonists (Cates 2008; Cates 2008a). In comparison to placebo treatment, adults on regular salmeterol and children on regular formoterol demonstrated a significant increase in all‐cause non‐fatal serious adverse events. Two additional reviews, in which each drug was randomised with an inhaled corticosteroid in comparison to the same dose of the inhaled corticosteroid, have been recently updated following completion of large trials mandated by the Food and Drug Administration (FDA) (Cates 2018; Janjua 2019).
These studies did not demonstrate significant increases in serious adverse events, but even with the addition of new trials, the confidence intervals are too wide to ensure that adding an inhaled corticosteroid renders regular long‐acting beta₂‐agonists completely safe. Moreover, indirect comparisons on the relative safety of formoterol and salmeterol based on the results of these existing reviews are subject to confounding due to differences among participants, interventions, comparisons, and outcomes in the trials in each review.
A review comparing the safety of regular formoterol and salmeterol without a randomised inhaled corticosteroid has also been carried out based on trials that have made head‐to‐head comparisons of the two products (Cates 2012). The trials that were included in Cates 2012 turned out to have used background inhaled corticosteroids for all participants. However, no previous review had compared regular formoterol to regular salmeterol from trials in which an inhaled corticosteroid was a mandatory part of the randomised treatment. We have considered this to be a separate question, as adherence with an inhaled corticosteroid may be better when it is provided as part of the randomised treatment schedule (particularly if a combined inhaler is used).
This review set out to compare the safety of regular formoterol and regular salmeterol when each is used in combination with a randomised inhaled corticosteroid.
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.
Methods
Criteria for considering studies for this review
Types of studies
We included controlled, parallel‐design clinical trials, with or without blinding, in which patients with chronic asthma were randomly assigned to regular treatment with formoterol and an inhaled corticosteroid versus salmeterol and an inhaled corticosteroid. We excluded studies on acute asthma and exercise‐induced bronchospasm.
Types of participants
We included patients of any age with a clinical diagnosis of asthma, unrestricted by disease severity or previous or current treatment.
Types of interventions
We included trials randomising patients to formoterol versus salmeterol given regularly in combination with an inhaled corticosteroid at any dose and delivered at a fixed dose by any single or separate devices (chlorofluorocarbon metered‐dose inhaler (CFC‐MDI); hydrofluoroalkane metered‐dose inhaler (HFA‐MDI); dry powder inhaler (DPI)) for a period of at least 12 weeks. We excluded studies that used adjustable maintenance dosing and single‐inhaler therapy (for maintenance and relief of symptoms).
Types of outcome measures
Primary outcomes
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All‐cause mortality
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All‐cause non‐fatal serious adverse events (see definition below)
Secondary outcomes
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Asthma‐related mortality
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Asthma‐related non‐fatal serious adverse events
We did not subdivide outcomes according to whether trial investigators considered them related to trial medication. We accepted trial investigators' judgement of whether or not serious adverse events were asthma‐related.
An assessment of efficacy outcomes (such as exacerbations, symptoms, and lung function) with these drug combinations when co‐delivered via the same inhaler has been undertaken and published elsewhere (Lasserson 2008).
Search methods for identification of studies
Electronic searches
The previously published version of this review included searches up to August 2011. For this update, we re‐ran the literature search from inception to February 2021 using the following databases and trial registries.
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Cochrane Airways Trials Register (Cochrane Airways 2019), via the Cochrane Register of Studies (all years to 24 February 2021).
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Cochrane Central Register of Controlled Trials (CENTRAL; 2021 Issue 2), in the Cochrane Library, via the Cochrane Register of Studies (all years to 24 February 2021).
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MEDLINE (Ovid SP) (ALL 1946 to 23 February 2021; searched 24 February 2021).
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Embase (Ovid SP) (1974 to week 7 2021; searched 24 February 2021).
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; all years to 24 February 2021).
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World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch; all years to 9 March 2020). This search was not updated in February 2021 as the platform was inaccessible at that time.
The initial search was conducted on 9 March 2020, and the search was updated on 24 February 2021. Search strategies are presented in Appendix 3. Population search terms were derived from the standard Cochrane Airways search strategy for asthma. Study design search terms are based on those recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2020). The search strategies were developed and searches conducted by the Cochrane Airways Information Specialist (ES). We did not restrict our searches by language or type of publication. We searched for conference abstracts and grey literature using the Cochrane Airways Trials Register, CENTRAL, and Embase.
Searching other resources
We checked the reference lists of all primary studies and review articles for additional references. We checked websites of clinical trial registers for unpublished trial data, and we checked FDA submissions related to salmeterol and formoterol. We searched for errata or retractions from included studies published in full text on PubMed, on 12 October 2020.
Data collection and analysis
Selection of studies
We used Cochrane’s Screen4Me workflow to assess the search results. Screen4Me comprises three components: known assessments – a service that matches records in the search results to records that have already been screened in Cochrane Crowd and been labelled as 'RCT' or 'not an RCT'; the RCT classifier – a machine learning model that distinguishes RCTs from non‐RCTs; and if appropriate, Cochrane Crowd – Cochrane’s citizen science platform whereby the Crowd helps to identify and describe health evidence.
For more information about Screen4Me and the evaluations that have been done, please go to the Screen4Me Web page on the Cochrane Information Specialist’s portal (https://community.cochrane.org/organizational-info/resources/resources-groups/information-specialists-portal). In addition, more detailed information regarding evaluations of the Screen4Me components can be found in the following publications: Marshall 2018, Thomas 2017, Noel‐Storr 2018, and McDonald 2017.
After completing this initial assessment, we imported the remaining references into Rayyan (Ouzzani 2016), and two review authors (OOS and CJC) independently assessed identified studies by examining titles, abstracts, and keyword fields. We obtained the full text of studies that potentially fulfilled the inclusion criteria. Two review authors (OOS and CJC) independently assessed full‐text articles for inclusion. No disagreements occurred.
Data extraction and management
Two review authors (OOS and CJC) extracted data independently using a prepared checklist and cross‐checked all data for accuracy. Data were entered by OOS into RevMan 5, and CJC checked entries for accuracy. We extracted data on characteristics (methods, participants, interventions, outcomes) and results of the included studies. We contacted study authors and sponsors of included studies for unpublished adverse event data and searched manufacturers' websites for further details of adverse events. We also searched FDA submissions. We recorded all‐cause serious adverse events (fatal and non‐fatal), and in view of the difficulty in deciding whether events are asthma‐related, noted details of the cause of death. We requested further information when causation was not clear (particularly in relation to serious adverse events).
Assessment of risk of bias in included studies
Two review authors (OOS and CJC) assessed the included studies for bias protection (including sequence generation for randomisation, allocation concealment, blinding of participants and assessors, loss to follow‐up, completeness of outcome assessment, and independent assessment of causation of serious adverse events). We judged risk of bias as high, low, or unclear according to recommendations in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011).
Measures of treatment effect
We used the definition of non‐fatal serious adverse events as provided by study authors, and given that most trials were carried out for regulatory purposes, we were confident that the following definitions were used.
Definition of serious adverse events
The Expert Working Group (Efficacy) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) defines a serious adverse event as follows (ICHE2A):
"a serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose:
-
results in death;
-
is life‐threatening;
-
requires inpatient hospitalisation or prolongation of existing hospitalisation;
-
results in persistent or significant disability/incapacity; or
-
is a congenital anomaly/birth defect.
NOTE: The term "life‐threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe.
Unit of analysis issues
We confined our analysis to patients with one or more serious adverse events rather than to the number of events that occurred (as the latter are not independent when one patient suffers multiple events). Moreover, the same event may be recorded under multiple categories, leading to risk of double‐counting of events.
Dealing with missing data
When serious adverse events were not fully reported in the published trial results, we contacted study authors and trial sponsors for further information.
Assessment of heterogeneity
We assessed heterogeneity by using the I²statisticto determine how much of the total heterogeneity found was between, rather than within, studies.
Assessment of reporting biases
We inspected funnel plots to assess publication bias for outcomes that included 10 or more studies with events.
Data synthesis
The outcomes of this review were dichotomous, and we recorded the numbers of participants with one or more of each outcome event by allocated treated group. We calculated pooled odds ratios (ORs). The Peto odds ratio has advantages when events are rare, as no adjustment for zero cells is required (Higgins 2020). This property was found in previous reviews to be more important than potential problems with unbalanced treatment arms; we therefore calculated the results for serious adverse events in RevMan 5 using the Peto method (with Mantel‐Haenszel methods for sensitivity analysis). We did not combine risk differences for this update, as this was not recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019).
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
Subgroup analysis and investigation of heterogeneity
We carried out subgroup analyses on the basis of age (adults versus children) using tests for interaction (Altman 2003). We did not attempt to combine the results from different formoterol combinations and did not carry out formal subgroup tests between them.
Sensitivity analysis
We carried out sensitivity analysis to assess the impact of the methods used to combine study events (Peto odds ratio and Mantel‐Haenszel odds ratio). We conducted sensitivity analyses on the degree of bias protection in study designs. When there were discrepant results between published papers and results published in trial registers, we used the data from papers in our primary analysis and carried out a sensitivity analysis using the results from registers. We also carried out a sensitivity analysis to exclude studies that used separate inhalers for formoterol and inhaled corticosteroids.
Summary of findings and assessment of the certainty of the evidence
We created a 'Summary of findings' table using the following outcomes: adults given formoterol and inhaled corticosteroid (ICS) compared to salmeterol and ICS: all‐cause mortality; adults given formoterol and ICS compared to salmeterol and ICS: all‐cause serious adverse events (SAEs); adults given formoterol and ICS compared to salmeterol and ICS: asthma‐related SAEs; and children given formoterol and fluticasone compared to salmeterol and fluticasone. We used the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to studies that contributed data for the pre‐specified outcomes. We used the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), along with GRADEpro software (GRADEpro GDT). We justified all decisions to downgrade the quality of studies by using footnotes, and we made comments to aid the reader's understanding of the review when necessary.
Results
Description of studies
Results of the search
We carried out the updated search for relevant studies up to February 2021 and identified a total of 1367 search results after duplicates were removed. In assessing these studies, we used Cochrane’s Screen4Me workflow to help identify potential reports of randomised trials. The results of Screen4Me assessments can be seen in Figure 1. We then assessed the remaining 906 records, and we obtained 51 abstracts as full articles. See Figure 2 for the PRISMA study flow diagram.
Screen4Me assessments, March 2020.
Study flow diagram.
We included 34 abstracts related to 13 new studies (Akamatsu 2014; Bernstein 2011; Emeryk 2016; EUCTR‐002587‐99‐CZ; EUCTR‐003449‐17‐IT; EUCTR‐004833‐70‐BG; Hsieh 2013; NCT00901368; Papi 2012; Ploszczuk 2014; Scichilone 2010; Usmani 2017; Woo 2020). We included as additional references 13 abstracts related to five existing studies (Busse 2008; Bodzenta‐Lukaszyk 2011; Kuna 2007; Maspero 2010; Papi 2007). We excluded three articles and provided reasons for their exclusion under Characteristics of excluded studies (NCT02491970; Rani 2016; UMIN000006572). We identified one study as ongoing (NCT03387241).
The review now includes a total of 23 studies. Twenty‐one studies included adults and adolescents; we refer to these hereafter as studies in adults. Two studies identified for the update included children only (Emeryk 2016; Ploszczuk 2014).
Included studies
We consider each combination of formoterol with a different inhaled corticosteroid in a separate subgroup; the details of dose and type of medication are summarised in Table 1.
| Study ID | Formoterol device | Formoterol dosea | ICS type and dosea | Salmeterol device | Salmeterol dosea | ICS type and dosea |
|---|---|---|---|---|---|---|
| DPI | 12 µg | Budesonide 400 µg | DPI | 50 µg | Fluticasone 250 µg | |
| DPI | 12 µg | Budesonide 400 µg | DPI | 50 µg | Flucticasone 250 µg | |
| pMDI | 12 µg | Beclomethasone extra‐fine 200 µg | DPI | 12 µg | Flucticasone 250 | |
| pMDI | 10 µg | Mometasone 200 µg | pMDI | 50 µg | Fluticasone 250 | |
| HFA pMDI with AeroChamber | 10 µg | Fluticasone 100 µg or 250 µg | HFA pMDI with AeroChamber | 50 µg | Fluticasone 100 µg or 250 µg | |
| pMDI | 12 µg | Budesonide 400 µg | DPI | 50 µg | Fluticasone 250 µg | |
| DPI | 12 µg | Budesonide 400 µg | DPI | 50 µg | Fluticasone 250 µg | |
| pMDI with AeroChamber | 10 µg | Fluticasone 100 µg | pMDI with AeroChamber | 50 µg | Fluticasone 100 µg | |
| pMDI (Foster) | 12 µg | Beclomethasone extra‐fine 200 µg | pMDI | 50 µg | Fluticasone 250 µg | |
| DPI | 12 µg | Budesonide 400 µg | pMDI | 50 µg | Fluticasone 250 µg | |
| pMDI | 10 µg | Mometasone 200 µg or 400 µg | pMDI | 50 µg | Fluticasone 250 µg or 500 µg | |
| pMDI | 12 µg | Beclomethasone extra‐fine 200 µg | pMDI | 50 µg | Fluticasone 250 µg | |
| pMDI (Foster) | 12 µg | Beclomethasone extra‐fine 200 µg | DPI | 50 µg | Flucticasone 250 µg | |
| pMDI | 10 µg | Fluticasone 100 µg | pMDI | 50 µg | Fluticasone 100 µg | |
| DPI 2 separate inhalers | 12 µg | Budesonide 800 µg | DPI | 50 µg | Fluticasone 250 µg | |
| DPI | 6 µg | Budesonide 200 µg | DPI | 50 µg | Fluticasone 100 µg | |
| DPI | 6 µg | Budesonide 200 µg | DPI | 50 µg | Fluticasone 250 µg | |
| pMDI (Foster) | 12 µg | Beclomethasone extra‐fine 200 µg | DPI | 50 µg | Fluticasone 250 µg | |
| pMDI | 20 µg | Fluticasone 500 µg | pMDI | 50 µg | Fluticasone 500 µg | |
| pMDI | 10 µg | Fluticasone 250 µg | DPI | 50 µg | Flucticasone 250 μg | |
| DPI | 12 µg | Budesonide 200 µg | DPI | 25 µg | Budesonide 150 µg | |
| pMDI | 12 µg | Beclomethasone 200 µg | DPI | 50 µg | Fluticasone 250 µg | |
| pMDI | 12 µg | Beclomethasone 400 µg | pMDI | 50 µg | Fluticasone 500 µg |
aAll doses taken twice daily.
Doses shown are ex‐actuator rather than delivered doses.
DPI: dry powder inhaler.
ICS: inhaled corticosteroid.
HFA: hydrofluoroalkane.
pMDI: pressurised metered‐dose inhaler.
Adults
Overall in eight studies, 7730 adults were randomised to formoterol and budesonide versus salmeterol and fluticasone (Aalbers 2004; Akamatsu 2014; Busse 2008; Dahl 2006; Kuna 2007; Ringdal 2002; SAM 40010; SAM 40048); in seven studies, 1472 adults were randomised to formoterol and extra‐fine beclomethasone versus salmeterol and fluticasone (EUCTR‐002587‐99‐CZ; EUCTR‐003449‐17‐IT; Hsieh 2013; NCT00901368; Papi 2007; Papi 2012; Scichilone 2010); in three studies, 1015 adults were randomised to formoterol and fluticasone or salmeterol and fluticasone (Bodzenta‐Lukaszyk 2011; Usmani 2017; Woo 2020); and in two studies, 1126 adults were randomised to formoterol and mometasone or salmeterol and fluticasone (Bernstein 2011; Maspero 2010). One study randomised 229 adults to formoterol and budesonide versus salmeterol and budesonide (EUCTR‐004833‐70‐BG).
Children
Two studies randomised 723 children to formoterol and fluticasone or salmeterol and fluticasone (Emeryk 2016; Ploszczuk 2014).
Doses and delivery devices
Details of delivery devices and doses of medication in each trial are given in Table 1. All studies used combination inhalers, except Ringdal 2002, in which formoterol and budesonide were administered in separate inhalers. We judged the dose of inhaled corticosteroid in each arm to be equivalent, except in Ringdal 2002 (higher‐dose budesonide) and SAM 40048 (higher‐dose fluticasone) (see Table 1). Although most studies compared 12 µg formoterol twice daily with 50 µg salmeterol twice daily, SAM 40010 and SAM 40048 compared 6 µg formoterol with 50 µg salmeterol twice daily. Usmani 2017 compared 20 µg formoterol twice daily with 50 µg salmeterol twice daily.
Run‐in period
Most studies continued their previous treatment with ICS alone during the run‐in period (those previously on long‐acting beta₂‐agonist (LABA) were excluded or discontinued LABA treatment), and patients were enrolled in the study if they were symptomatic at the end of run‐in. Busse 2008 allowed ICS and LABA/ICS to be continued during run‐in, but participants still had to be symptomatic to be enrolled into the study. Bodzenta‐Lukaszyk 2011 did not specify treatment details for the screening phase of 4 to 10 days to evaluate eligibility, and Maspero 2010 kept participants on their previous medication during screening. Akamatsu 2014 and Papi 2012 were step‐down studies in which participants continued combination treatment during the 8‐week run‐in.
In the studies included for the 2020 update, nearly all participants had been using a LABA/ICS before randomisation. EUCTR‐004833‐70‐BG, Hsieh 2013, Ploszczuk 2014, and Scichilone 2010 did not include a run‐in period in which participants used a LABA nor specify that participants had been using a LABA before randomisation. In Emeryk 2016, most participants (83.8% and 86.8% in each group) had been using a LABA before randomisation.
Age of participants
In adult studies, the lower age limit varied from 12 years old in Aalbers 2004, SAM 40010, SAM 40048, Kuna 2007, Busse 2008 and Maspero 2010, to 16 or 18 years old in Ringdal 2002, Dahl 2006, Papi 2007 and Bodzenta‐Lukaszyk 2011.
In studies of children, participant age ranged from 4 to 12 years and from 5 to 12 years, respectively ‐ in Ploszczuk 2014 and Emeryk 2016.
Sponsorship and location
Almost all included studies were sponsored by one of the manufacturers of combined inhalers, and the duration and locations of studies are shown in Table 2. Sponsorship for Akamatsu 2014 is not known.
| Study ID | Number randomised | Duration (weeks) | Age (years) | Location | Sponsors |
|---|---|---|---|---|---|
| 658 | 26 (open‐extension) | 12+ | Europe | AstraZeneca | |
| 66 | 12 | 18+ | Japan | Unknown | |
| 431 | 12 | 18 to 65 | Europe | Chiesi Farmaceutici S.p.A. | |
| 722 | 12 | 12+ | No location details provided | Merck Sharp & Dohme Corp. | |
| 202 | 12 | 18+ | Europe | Mundipharma | |
| 1225 | 30 | 12+ | USA | AstraZeneca | |
| 1397 | 24 | 18+ | Europe | GlaxoSmithKline | |
| 211 | 12 | 4 to 12 | Europe | Mundipharma Research Limited | |
| 253 | 12 | 20 to 65 | Taiwan | Orient EuroPharma Co., Ltd., Taiwan. | |
| 3335 | 24 | 12+ | Multi‐national | AstraZeneca | |
| 404 | 52 | 12+ | South America | Merck | |
| 228 | 12 | 18+ | Europe | Chiesi | |
| 422 | 24 | 18 to 65 | Europe | Chiesi Farmaceutici S.p.A. | |
| 512 | 12 | 5 to 2 | Euope and India | Mundipharma | |
| 428 | 12 | 16+ | Europe | GlaxoSmithKline | |
| 373 | 12 | 12+ | Europe | GlaxoSmithKline | |
| 248 | 12 | 18+ | Germany | GlaxoSmithKline | |
| 30 | 12 | 18 to 50 | Italy | Chiesi Farmaceutici S.p.A. | |
| 225 | 24 | 18 to 75 | England | Research in Real Life & Napp | |
| 68 | 12 | 55+ | Korea | Mundipharma Korea | |
| 229 | 12 | 18 to 65 | Bulgaria, Serbia, Romania, Macedonia | Laboratoires SMB S.A. | |
| 108 | 12 | No details | Italy | Chiesi Farmaceutici S.p.A. | |
| 481a | 24 | 12 to 84 | Poland, Slovenia, Spain, Bulgaria, Czech Republic, Estonia, France, Germany, Hungary, Italy, Latvia, Lithuania, Belarus, Croatia, Romania, Russian Federation Ukraine | Chiesi Farmaceutici S.p.A. |
aThird arm not included.
Excluded studies
We listed the excluded studies under Characteristics of excluded studies along with reasons for exclusion.
Risk of bias in included studies
Figure 3 shows an overview of the potential risks of bias in each study.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Allocation
We judged sequence generation and allocation concealment to be adequate in 10 studies (Aalbers 2004; Bodzenta‐Lukaszyk 2011; Busse 2008; Dahl 2006; Emeryk 2016; Kuna 2007; Papi 2007; Papi 2012; Ploszczuk 2014; Ringdal 2002). Methods used were not clearly reported in the other studies, but we regarded it as likely that this was a reporting issue, as sponsored studies tended to be at low risk of selection bias.
Blinding
Eleven studies had well‐reported methods of blinding (Dahl 2006; EUCTR‐002587‐99‐CZ; EUCTR‐003449‐17‐IT; Hsieh 2013; Kuna 2007; NCT00901368; Papi 2007; Ringdal 2002; SAM 40010; SAM 40048; Scichilone 2010), and 12 studies were open‐label (Aalbers 2004; Akamatsu 2014; Bernstein 2011; Bodzenta‐Lukaszyk 2011; Busse 2008; Emeryk 2016; EUCTR‐004833‐70‐BG; Maspero 2010; Papi 2012; Ploszczuk 2014; Usmani 2017; Woo 2020), but one study reported evaluator blinding (Maspero 2010). All studies were judged to be at low risk of bias with regard to detection bias for all‐cause events, regardless of blinding, because blinding did not impact the assessment of all‐cause outcomes.
Incomplete outcome data
All studies, with the exception of Aalbers 2004Bernstein 2011, and Scichilone 2010, reported that at least 80% of participants completed the study, and in most cases, the completion rate was 90% or above (see Characteristics of included studies for details of individual studies). Usmani 2017 was judged to have high risk of bias with regard to attrition bias due to the discrepancy in dropouts between the two groups (88.7% and 98.6% completion, respectively). Bernstein 2011 was also judged to have high risk of bias with regard to attrition bias, as > 40% dropouts were reported across the two groups (41% and 42%, respectively).
Selective reporting
Following correspondence with study authors and funders, we obtained full data on all‐cause SAEs from all studies, with the exception of Akamatsu 2014, Scichilone 2010, Hsieh 2013, and NCT00901368.
Other potential sources of bias
Almost all studies have been sponsored by manufacturers of combined long‐acting beta₂‐agonists and ICS inhalers. None of the studies had an independent assessment of the cause of SAEs, which we regard as having high risk of bias when asthma‐related events (rather than all‐cause events) are considered.
Effects of interventions
See: Summary of findings 1 Adults: formoterol/ICS compared to salmeterol/ICS for chronic asthma: all‐cause mortality; Summary of findings 2 Adults: formoterol/ICS compared to salmeterol/ICS for chronic asthma: all‐cause serious adverse events; Summary of findings 3 Adults: formoterol/ICS compared to salmeterol/ICS for chronic asthma: asthma‐related serious adverse events; Summary of findings 4 Children: formoterol/fluticasone compared to salmeterol/fluticasone for chronic asthma: serious adverse events
Adults
No asthma‐related deaths were reported in any of the included studies, and not enough deaths were considered as cardiovascular‐related mortality (which was a secondary outcome in our protocol). Therefore, we analysed all‐cause mortality and listed the recorded causation of each death narratively in the text.
Formoterol/budesonide versus salmeterol/fluticasone
Mortality
Two deaths were reported in 5935 adult and adolescent participants; neither was asthma‐related. In SAM 40010, there was one death in the formoterol/budesonide group due to gastrointestinal obstruction, cardiac failure, and septic shock. In Kuna 2007, one death in the salmeterol/fluticasone group was due to cardiac failure. Pooled results show there may be little to no difference in all‐cause mortality between groups (Peto odds ratio (OR) 1.03; 95% confidence interval (CI) 0.06 to 16.44; I² = 50%; see Figure 4); however this is low‐certainty evidence, as the confidence intervals are very wide.
Forest plot of comparison: 1 Fixed‐dose formoterol/ICS versus salmeterol/fluticasone, outcome: 1.1 All‐cause mortality.
All‐cause non‐fatal serious adverse events
In all, 77 out of 2966 adults and adolescents on formoterol and budesonide suffered one or more SAEs, compared to 68 out of 2969 patients on salmeterol and fluticasone. There is probably little to no difference in SAEs between groups (Peto OR 1.14, 95% CI 0.82 to 1.59; I² = 26%; see Figure 5); however the confidence interval is too wide to conclude that risks are the same for each treatment.
Forest plot of comparison: 1 Fixed‐dose formoterol/ICS versus salmeterol/fluticasone, outcome: 1.2 All‐cause non‐fatal serious adverse events.
Busse 2008 reported that nine participants suffered an SAE in each arm of the trial (Table S4 of the paper), but one additional participant on formoterol/budesonide was admitted to hospital on treatment for an episode that was judged to have started during run‐in. Another participant had an SAE after the last dose of randomised treatment, but correspondence with the sponsors revealed that this participant had already suffered an SAE on treatment, and so was already included. We therefore decided to enter 10 participants for the formoterol/budesonide arm of this trial. We carried out a sensitivity analysis to assess the impact of excluding the additional patient in the formoterol/budesonide arm, and results show very little difference in the odds ratio (Peto OR 1.08, 95% CI 0.80 to 1.46; see Figure 6).
Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.1 Busse SAE sensitivity analysis.
Asthma‐related non‐fatal serious adverse events
For two studies, we were not able to find published reports on the number of patients who had experienced one or more asthma‐related SAEs, but we were able to obtain this information from the sponsor (Busse 2008; Kuna 2007). Overall 17 adults and adolescents out of 2966 on formoterol and budesonide had asthma‐related SAEs, as did 25 out of 2969 on salmeterol and fluticasone. Risk of asthma‐related events may be numerically lower with formoterol/budesonide (Peto OR 0.69, 95% CI 0.37 to 1.26; I² = 33%; see Figure 7), but no independent outcome assessment was performed and the confidence interval is wide, so we regard this as low‐certainty evidence.
Forest plot of comparison: 1 Fixed‐dose formoterol/ICS versus salmeterol/fluticasone, outcome: 1.3 Asthma‐related non‐fatal serious adverse events.
The number of patients in Dahl 2006 admitted to hospital on salmeterol and fluticasone was recorded as four, which is lower than the six patients recorded as having asthma‐related SAEs in this review. The reason for this difference has been clarified following correspondence with GlaxoSmithKline and is related to one patient who experienced acute bronchospasm but was not admitted to hospital, and a second patient who was admitted to hospital but had an exacerbation that had started during the run‐in period.
Formoterol/beclomethasone versus salmeterol/fluticasone
Mortality
No deaths were reported in four studies; Scichilone 2010, NCT00901368, and Hsieh 2013 did not provide any data on mortality.
All‐cause non‐fatal serious adverse events
A total of 12 all‐cause non‐fatal SAEs were reported among 960 adolescent and adult participants in the formoterol group, and 13 all‐cause non‐fatal SAEs among 981 adolescent and adult participants in the salmeterol group. In the formoterol arm, there was one all‐cause non‐fatal SAE in EUCTR‐003449‐17‐IT (bronchopneumonia), one in Papi 2012, two in NCT00901368, three in Hsieh 2013, and five in EUCTR‐002587‐99‐CZ (fractured neck of femur, atrial fibrillation, anaemia, calculus urinary, and one asthma‐related). In the salmeterol arm, there were three all‐cause non‐fatal SAEs in Papi 2012, four in Hsieh 2013, and four in EUCTR‐002587‐99‐CZ. Scichilone 2010 did not provide any data on all‐cause non‐fatal SAEs. There is probably little to no difference in SAEs between groups (Peto OR 0.94, 95% CI 0.43 to 2.08; see Figure 5), but again, the confidence interval is too wide to conclude that risks are same for each treatment.
Asthma‐related non‐fatal serious adverse events
There were two asthma‐related SAEs: one in 533 adolescent and adult participants in the formoterol arm, and one in 537 adolescent and adult participants the salmeterol arm. Both of these occurred in EUCTR‐002587‐99‐CZ. NCT00901368 and Scichilone 2010 did not provide any data on asthma‐related SAEs. There may be little to no difference in non‐fatal SAEs between groups (Peto OR 1.01, 95% CI 0.06 to 16.24; see Figure 7), but as there were only two events and no independent outcome assessment, the evidence is very uncertain.
Formoterol/mometasone versus salmeterol/fluticasone
Mortality
Two deaths occurred in the formoterol/mometasone arm of Maspero 2010 (see Figure 4). One death was due to electrocution, and one due to gastric cancer. No deaths occurred in Bernstein 2011. Treatment with formoterol/mometasone may involve greater risk (Peto OR 4.46, 95% CI 0.23 to 85.40; see Figure 4), but with only two deaths in total, this is low‐certainty evidence with a very wide confidence interval.
All‐cause non‐fatal serious adverse events
Similar proportions of participants with non‐fatal SAEs of any cause were reported for both formoterol/mometasone (n = 18 participants) and salmeterol/fluticasone (n = 11 participants). Available evidence shows there is probably little to no difference in non‐fatal SAEs between formoterol and salmeterol (Peto OR 1.02, 95% CI 0.47 to 2.20; see Figure 5), but the confidence intervals are too wide to conclude that the safety of the two products is equivalent. Similarly, Bernstein 2011 reported five non‐fatal SAEs in each arm of the trial; however EU Clinical Trials (EUCT) and National Clinical Trial (NCT) websites report six and eight SAEs per group. We carried out a sensitivity analysis to assess the impact of excluding the additional SAEs reported at EUCT and NCT websites, which showed a similar odds ratio (Peto OR 0.88, 95% CI 0.43 to 1.81; see Figure 8).
Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.2 Bernstein SAE sensitivity analysis.
Asthma‐related serious adverse events
One asthma‐related SAE was reported in Bernstein 2011 among 371 participants in the formoterol arm (Peto OR 7.00, 95% CI 0.14 to 353.37; see Figure 7). With only one event, the evidence on differences between groups in risk of asthma‐related SAEs is very uncertain.
Formoterol/fluticasone versus salmeterol/fluticasone
Mortality
One death from haemorrhagic stroke and cardiac arrest occurred in the formoterol arm with 101 participants in Bodzenta‐Lukaszyk 2011. No deaths occurred in Woo 2020, and Usmani 2017 did not provide any data on mortality. With only a single death, evidence on differences between groups in risk of death is uncertain (Peto OR 7.39, 95% CI 0.15 to 372.38; see Figure 4).
All‐cause non‐fatal serious adverse events
One all‐cause non‐fatal SAE (pneumonia) was reported in the salmeterol arm of Usmani 2017, with 74 participants. None occurred in Woo 2020, and Bodzenta‐Lukaszyk 2011 did not provide any data on this. Again with a single event, the evidence on differences between groups in risk of all‐cause non‐fatal SAEs is uncertain (Peto OR 0.05, 95% CI 0.00 to 3.10; see Figure 5).
Asthma‐related serious adverse events
One asthma non‐fatal SAE (pneumonia) was reported in the salmeterol arm of Usmani 2017, with 74 participants. None occurred in Woo 2020, and Bodzenta‐Lukaszyk 2011 did not provide any data on this. With a single event and no independent outcome assessment, the evidence on differences in risk between groups is very uncertain (Peto OR 0.05, 95% CI 0.00 to 3.10; see Figure 7).
Formoterol/budesonide versus salmeterol/budesonide
No deaths occurred and one all‐cause non‐fatal SAE was reported in the formoterol arm among 114 participants (EUCTR‐004833‐70‐BG). This non‐fatal SAE was not thought to be asthma‐related (Peto OR 7.45, 95% CI 0.15 to 375.68; see Figure 5). As only a single event was reported, we are unable to make any meaningful comparison of the relative safety of the two treatments.
Children
Formoterol/fluticasone versus salmeterol/fluticasone
Mortality
No deaths were reported in either of the children's studies (Emeryk 2016; Ploszczuk 2014).
All‐cause non‐fatal serious adverse events
Three all‐cause non‐fatal SAEs were reported in the formoterol arm among 274 participants: two appendicitis (Emeryk 2016), and one bronchitis (Ploszczuk 2014). One all‐cause non‐fatal SAE was reported in the salmeterol group among 274 participants. One case of pneumonia occurred in Emeryk 2016. Although risk of SAE may be higher in children on formoterol/fluticasone (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; I² = 0%; see Figure 9), the very wide confidence intervals mean that this is low‐certainty evidence.
Forest plot of comparison: 2 Children formoterol/fluticasone versus salmeterol/fluticasone, outcome: 2.2 All‐cause non‐fatal serious adverse events.
Asthma‐related serious adverse events
No asthma‐related SAEs were reported in either of the children's studies (Emeryk 2016; Ploszczuk 2014).
Sensitivity analysis
We carried out sensitivity analysis while excluding the single study that used separate inhalers for formoterol and ICS (Ringdal 2002); this made little difference in all‐cause non‐fatal SAEs (Peto OR 1.08, 95% CI 0.80 to 1.47; 6633 participants, 8 studies).
We carried out sensitivity analysis while excluding the two unblinded studies in the formoterol/budesonide versus salmeterol/fluticasone comparison (Aalbers 2004; Busse 2008). Restricting the analysis to blinded studies had no impact on mortality (as no deaths were reported in either of the open studies). All‐cause SAEs in the blinded studies showed no important change (OR 1.05, 95% CI 0.72 to 1.53; I² = 20%; see Figure 10), and similarly, asthma‐related events were not much altered (OR 0.74, 95% CI 0.39 to 1.40; I² = 0%; see Figure 11).
Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.3 All‐cause non‐fatal SAE blinding.
Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.4 Asthma‐related non‐fatal SAE blinding.
We conducted a sensitivity analysis while excluding one unblinded study in the formoterol/beclomethasone versus salmeterol/fluticasone comparison (Papi 2012). This analysis was restricted to all SAEs and asthma‐related SAEs (as there were no deaths in this study). All‐cause SAEs in the blinded studies showed little change from the analysis of all studies (OR 1.11, 95% CI 0.48 to 2.59; I² = 0%; see Figure 8), and similarly, asthma‐related events were not much changed (OR 1.01, 95% CI 0.06 to 16.28; I² = 0%; Figure 11).
We conducted another sensitivity analysis while excluding one unblinded study from the formoterol/mometasone versus salmeterol/fluticasone comparison (Maspero 2010). This analysis was restricted to all‐cause SAEs, as this study did not report any asthma‐related SAEs, and no deaths were reported in the remaining study in the subgroup (Bernstein 2011). These analyses showed little change (OR 0.95, 95% CI 0.27 to 3.29; I² = 0%; Figure 5).
Subgroup analysis
We conducted subgroup analysis to compare the studies in adults and children for all‐cause non‐fatal SAEs with formoterol/fluticasone versus salmeterol/fluticasone. The test for subgroup difference was negative (Chi² = 2.95; df = 1 (P = 0.09); I² = 66.1%; see Analysis 2.4).
We did not attempt to conduct subgroup analysis on the basis of dose equivalence of ICS or long‐acting beta₂‐agonists, as the data were too sparse.
Publication bias
A funnel plot is shown for all‐cause SAEs in Figure 12, suggesting no small‐study effects nor publication bias.
Funnel plot of comparison: 1 Adults formoterol/ICS versus salmeterol/ICS, outcome: 1.2 All‐cause non‐fatal serious adverse events.
Discussion
Summary of main results
We identified 13 new studies in the updated search; in total, we included 23 studies in this review. Two studies were not included in the analysis, as results were not available. Nineteen studies contributing to the analysis involved adults and adolescents. Seven of these (N = 5935) compared formoterol and budesonide to salmeterol and fluticasone. Four studies (N = 1239) compared formoterol and beclomethasone to salmeterol and fluticasone; two (N = 1126) compared formoterol and mometasone to salmeterol and fluticasone; three (N = 1015) compared formoterol and fluticasone with salmeterol and fluticasone; and one (N = 229) compared formoterol and budesonide to salmeterol and budesonide. We identified two studies in children (N = 723), both of which compared formoterol and fluticasone to salmeterol and fluticasone. These studies recruited participants who were previously treated with moderate to high doses of inhaled steroids (with or without salmeterol or formoterol). All studies except Ringdal 2002 used combination inhalers.
We did not identify any certain differences between combination treatment on formoterol with inhaled corticosteroids (ICS) and salmeterol with fluticasone or budesonide for all‐cause mortality, non‐fatal adverse events of any cause, or events related to asthma. However the confidence intervals are wide, so we cannot rule out differences between formoterol and salmeterol combination inhalers.
Overall completeness and applicability of evidence
Although the included studies were sufficiently powered for equivalence in terms of the primary efficacy outcomes (e.g. Papi 2007), they remain underpowered to detect possible important differences in serious adverse events (SAEs) (Cates 2008). Therefore, although no certain differences have been found between combination inhalers, the confidence intervals are too wide to indicate equivalence of safety.
Quality of the evidence
The included studies were generally well protected against bias (see Figure 3). Allocation concealment and sequence generation did not present undue risk of bias in the included studies, and results on SAEs have been obtained from all studies except Akamatsu 2014 and Scichilone 2010 (total of 96 participants). Aalbers 2004, Busse 2008, Bodzenta‐Lukaszyk 2011, and Maspero 2010 were open studies, and Aalbers 2004 had a withdrawal rate of over 20%. We carried out sensitivity analysis using only blinded studies and found little change in the results. Consideration of asthma‐related adverse events was at higher risk of bias, as none of the trials used independent outcome assessment for causation of adverse events.
Potential biases in the review process
Given that the included studies were designed to assess efficacy, it seems unlikely that publication bias would take the form of whole studies remaining unreported. However, it is apparent that reporting of SAEs in medical journals is sub‐optimal (Cates 2008). For this review, it has been possible to obtain SAE data from all but two studies, following correspondence with trial sponsors. We therefore believe there is low risk of publication bias for this review, and the funnel plot was unremarkable (Figure 12).
Agreements and disagreements with other studies or reviews
Previous reviews have identified increased risk of SAEs with regular salmeterol (Cates 2008), and with regular formoterol (Cates 2008a), when compared to placebo. In contrast, in studies that used randomised inhaled corticosteroids, no significant increase in SAEs has been shown with regular combination salmeterol (Cates 2018), nor with regular combination formoterol (Janjua 2019). However, the confidence intervals in the latter reviews are too wide to conclude that adding an ICS renders regular combination formoterol or salmeterol completely safe, even with with the recent inclusion of four very large trials (Peters 2016; Stempel 2016; Stempel 2016a; Weinstein 2019). It is in keeping with these latter reviews that we have found no certain differences between regular combination formoterol and salmeterol. The results of this review are similar to those of Cates 2012, which found no significant differences between formoterol and salmeterol when all participants used background (rather than randomised) ICS.
The negative findings may be due in part to statistical power, as very large numbers of patients would need to be randomised to identify small differences between combination formoterol and salmeterol. We do not have enough information to make meaningful safety comparisons between the different formoterol/salmeterol and ICS combinations.
Screen4Me assessments, March 2020.
Study flow diagram.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Forest plot of comparison: 1 Fixed‐dose formoterol/ICS versus salmeterol/fluticasone, outcome: 1.1 All‐cause mortality.
Forest plot of comparison: 1 Fixed‐dose formoterol/ICS versus salmeterol/fluticasone, outcome: 1.2 All‐cause non‐fatal serious adverse events.
Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.1 Busse SAE sensitivity analysis.
Forest plot of comparison: 1 Fixed‐dose formoterol/ICS versus salmeterol/fluticasone, outcome: 1.3 Asthma‐related non‐fatal serious adverse events.
Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.2 Bernstein SAE sensitivity analysis.
Forest plot of comparison: 2 Children formoterol/fluticasone versus salmeterol/fluticasone, outcome: 2.2 All‐cause non‐fatal serious adverse events.
Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.3 All‐cause non‐fatal SAE blinding.
Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.4 Asthma‐related non‐fatal SAE blinding.
Funnel plot of comparison: 1 Adults formoterol/ICS versus salmeterol/ICS, outcome: 1.2 All‐cause non‐fatal serious adverse events.
Comparison 1: Adults formoterol/ICS versus salmeterol/ICS, Outcome 1: All‐cause mortality
Comparison 1: Adults formoterol/ICS versus salmeterol/ICS, Outcome 2: All‐cause non‐fatal serious adverse events
Comparison 1: Adults formoterol/ICS versus salmeterol/ICS, Outcome 3: Asthma related non‐fatal serious adverse events
Comparison 2: Children formoterol/fluticasone versus salmeterol/fluticasone, Outcome 1: All‐cause mortality
Comparison 2: Children formoterol/fluticasone versus salmeterol/fluticasone, Outcome 2: All‐cause non‐fatal serious adverse events
Comparison 2: Children formoterol/fluticasone versus salmeterol/fluticasone, Outcome 3: Asthma related non‐fatal serious adverse events
Comparison 2: Children formoterol/fluticasone versus salmeterol/fluticasone, Outcome 4: All‐cause non‐fatal serious adverse events
Comparison 3: Sensitivity analysis, Outcome 1: Busse SAE sensitivity analysis
Comparison 3: Sensitivity analysis, Outcome 2: Bernstein SAE sensitivity analysis
Comparison 3: Sensitivity analysis, Outcome 3: All‐cause non‐fatal SAE blinding
Comparison 3: Sensitivity analysis, Outcome 4: Asthma‐related non‐fatal SAE blinding
Comparison 3: Sensitivity analysis, Outcome 5: Single‐inhaler SAE sensitivity analysis
| Adults formoterol/ICS compared to salmeterol/ICS for chronic asthma: all‐cause mortality | ||||||
| Patient or population: adults, chronic asthma: all‐cause mortality | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | №. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with salmeterol/ICS | Risk with formoterol/ICS | |||||
| All‐cause mortality ‐ formoterol/budesonide vs salmeterol/fluticasone | 34 per 100,000 | 35 per 100,000 | OR 1.03 | 5935 | ⊕⊕⊝⊝ | |
| All‐cause mortality ‐ formoterol/beclomethasone vs salmeterol/fluticasone | No deaths | ‐ | 1257 | N/A | ||
| All‐cause mortality ‐ formoterol/mometasone vs salmeterol/fluticasone | 0 per 100,000 | 0 per 100,000 | OR 4.46 | 1126 | ⊕⊕⊝⊝ | Zero events on salmeterol prevents calculation of absolute risk |
| All‐cause mortality ‐ formoterol/fluticasone vs salmeterol/fluticasone | 0 per 100,000 | 0 per 100,000 | OR 7.39 | 270 | ⊕⊕⊝⊝ | Zero events on salmeterol prevents calculation of absolute risk |
| All‐cause mortality formoterol/budesonide vs salmeterol/budesonide Follow‐up: mean 12 weeks | No deaths | ‐ | 229 (1 RCT) | N/A | ||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aVery wide confidence interval, downgraded by 2 points. | ||||||
| Adults: formoterol/ICS compared to salmeterol/ICS for chronic asthma: all‐cause serious adverse events | ||||||
| Patient or population: adults, chronic asthma: serious adverse events | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | №. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with salmeterol/ICS | Risk with formoterol/ICS | |||||
| All‐cause non‐fatal serious adverse events ‐ formoterol/budesonide vs salmeterol/fluticasone | 2290 per 100,000 | 2603 per 100,000 | OR 1.14 | 5935 | ⊕⊕⊕⊝ | |
| All‐cause non‐fatal serious adverse events ‐ formoterol/beclomethasone vs salmeterol/fluticasone | 1325 per 100,000 | 1247 per 100,000 | OR 0.94 | 1941 | ⊕⊕⊕⊝ | |
| All‐cause non‐fatal serious adverse events ‐ formoterol/mometasone vs salmeterol/fluticasone | 2273 per 100,000 | 2317 per 100,000 | OR 1.02 | 1126 | ⊕⊕⊕⊝ | |
| All‐cause non‐fatal serious adverse events ‐ formoterol/fluticasone vs salmeterol/fluticasone | 935 per 100,000 | 47 per 100,000 | OR 0.05 | 293 | ⊕⊕⊝⊝ | |
| All‐cause non‐fatal serious adverse events ‐ formoterol/budesonide vs salmeterol/budesonide | 0 per 100,000 | 0 per 100,000 | OR 7.45 | 229 | ⊕⊕⊝⊝ | Zero events on salmeterol prevents calculation of absolute risk |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aConfidence interval wide, downgraded by 1 point. bConfidence interval very wide, downgraded by 2 points. | ||||||
| Adults: formoterol/ICS compared to salmeterol/ICS for chronic asthma: asthma‐related serious adverse events | ||||||
| Patient or population: adults, chronic asthma: asthma‐related serious adverse events | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | №. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with salmeterol/ICS | Risk with formoterol/ICS | |||||
| Asthma‐related non‐fatal serious adverse events ‐ formoterol/budesonide vs salmeterol/fluticasone | 842 per 100,000 | 583 per 100,000 | OR 0.69 | 5935 | ⊕⊕⊝⊝ | |
| Asthma‐related non‐fatal serious adverse events ‐ formoterol/beclomethasone vs salmeterol/fluticasone | 131 per 100,000 | 132 per 100,000 | OR 1.01 | 1510 | ⊕⊝⊝⊝ | |
| Asthma related non‐fatal serious adverse events ‐ formoterol/mometasone v's salmeterol/fluticasone | 0 per 100,000 | 0 per 100,000 | OR 7.00 | 722 | ⊕⊝⊝⊝ | Zero events on salmeterol prevents calculation of absolute risk |
| Asthma‐related non‐fatal serious adverse events ‐ formoterol/fluticasone vs salmeterol/fluticasone | 935 per 100,000 | 47 per 100,000 | OR 0.05 | 293 | ⊕⊕⊝⊝ | |
| Asthma‐related non‐fatal serious adverse events ‐ formoterol/budesonide vs salmeterol/budesonide | 0 per 100,000 | 0 per 100,000 | Not estimable | 229 | N/A | No events |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aConfidence interval wide, downgraded by 1 point. bNo independent assessment of causation, downgraded by 1 point. cConfidence interval very wide, downgraded by 2 points. | ||||||
| Children: formoterol/fluticasone compared to salmeterol/fluticasone for chronic asthma: serious adverse events | ||||||
| Patient or population: children, chronic asthma: serious adverse events | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | №. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with salmeterol/fluticasone | Risk with formoterol/fluticasone | |||||
| All‐cause mortality | No deaths
| ‐ | 548 | N/A | ||
| All‐cause non‐fatal serious adverse events | 365 per 100,000 | 987 per 100,000 | OR 2.72 | 548 | ⊕⊕⊝⊝ | |
| Asthma‐related non‐fatal serious adverse events | No asthma‐related events | ‐ | 548 | N/A | ||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aVery wide confidence interval, downgraded by 2 points. | ||||||
| Study ID | Formoterol device | Formoterol dosea | ICS type and dosea | Salmeterol device | Salmeterol dosea | ICS type and dosea |
|---|---|---|---|---|---|---|
| DPI | 12 µg | Budesonide 400 µg | DPI | 50 µg | Fluticasone 250 µg | |
| DPI | 12 µg | Budesonide 400 µg | DPI | 50 µg | Flucticasone 250 µg | |
| pMDI | 12 µg | Beclomethasone extra‐fine 200 µg | DPI | 12 µg | Flucticasone 250 | |
| pMDI | 10 µg | Mometasone 200 µg | pMDI | 50 µg | Fluticasone 250 | |
| HFA pMDI with AeroChamber | 10 µg | Fluticasone 100 µg or 250 µg | HFA pMDI with AeroChamber | 50 µg | Fluticasone 100 µg or 250 µg | |
| pMDI | 12 µg | Budesonide 400 µg | DPI | 50 µg | Fluticasone 250 µg | |
| DPI | 12 µg | Budesonide 400 µg | DPI | 50 µg | Fluticasone 250 µg | |
| pMDI with AeroChamber | 10 µg | Fluticasone 100 µg | pMDI with AeroChamber | 50 µg | Fluticasone 100 µg | |
| pMDI (Foster) | 12 µg | Beclomethasone extra‐fine 200 µg | pMDI | 50 µg | Fluticasone 250 µg | |
| DPI | 12 µg | Budesonide 400 µg | pMDI | 50 µg | Fluticasone 250 µg | |
| pMDI | 10 µg | Mometasone 200 µg or 400 µg | pMDI | 50 µg | Fluticasone 250 µg or 500 µg | |
| pMDI | 12 µg | Beclomethasone extra‐fine 200 µg | pMDI | 50 µg | Fluticasone 250 µg | |
| pMDI (Foster) | 12 µg | Beclomethasone extra‐fine 200 µg | DPI | 50 µg | Flucticasone 250 µg | |
| pMDI | 10 µg | Fluticasone 100 µg | pMDI | 50 µg | Fluticasone 100 µg | |
| DPI 2 separate inhalers | 12 µg | Budesonide 800 µg | DPI | 50 µg | Fluticasone 250 µg | |
| DPI | 6 µg | Budesonide 200 µg | DPI | 50 µg | Fluticasone 100 µg | |
| DPI | 6 µg | Budesonide 200 µg | DPI | 50 µg | Fluticasone 250 µg | |
| pMDI (Foster) | 12 µg | Beclomethasone extra‐fine 200 µg | DPI | 50 µg | Fluticasone 250 µg | |
| pMDI | 20 µg | Fluticasone 500 µg | pMDI | 50 µg | Fluticasone 500 µg | |
| pMDI | 10 µg | Fluticasone 250 µg | DPI | 50 µg | Flucticasone 250 μg | |
| DPI | 12 µg | Budesonide 200 µg | DPI | 25 µg | Budesonide 150 µg | |
| pMDI | 12 µg | Beclomethasone 200 µg | DPI | 50 µg | Fluticasone 250 µg | |
| pMDI | 12 µg | Beclomethasone 400 µg | pMDI | 50 µg | Fluticasone 500 µg | |
| aAll doses taken twice daily. Doses shown are ex‐actuator rather than delivered doses. DPI: dry powder inhaler. | ||||||
| Study ID | Number randomised | Duration (weeks) | Age (years) | Location | Sponsors |
|---|---|---|---|---|---|
| 658 | 26 (open‐extension) | 12+ | Europe | AstraZeneca | |
| 66 | 12 | 18+ | Japan | Unknown | |
| 431 | 12 | 18 to 65 | Europe | Chiesi Farmaceutici S.p.A. | |
| 722 | 12 | 12+ | No location details provided | Merck Sharp & Dohme Corp. | |
| 202 | 12 | 18+ | Europe | Mundipharma | |
| 1225 | 30 | 12+ | USA | AstraZeneca | |
| 1397 | 24 | 18+ | Europe | GlaxoSmithKline | |
| 211 | 12 | 4 to 12 | Europe | Mundipharma Research Limited | |
| 253 | 12 | 20 to 65 | Taiwan | Orient EuroPharma Co., Ltd., Taiwan. | |
| 3335 | 24 | 12+ | Multi‐national | AstraZeneca | |
| 404 | 52 | 12+ | South America | Merck | |
| 228 | 12 | 18+ | Europe | Chiesi | |
| 422 | 24 | 18 to 65 | Europe | Chiesi Farmaceutici S.p.A. | |
| 512 | 12 | 5 to 2 | Euope and India | Mundipharma | |
| 428 | 12 | 16+ | Europe | GlaxoSmithKline | |
| 373 | 12 | 12+ | Europe | GlaxoSmithKline | |
| 248 | 12 | 18+ | Germany | GlaxoSmithKline | |
| 30 | 12 | 18 to 50 | Italy | Chiesi Farmaceutici S.p.A. | |
| 225 | 24 | 18 to 75 | England | Research in Real Life & Napp | |
| 68 | 12 | 55+ | Korea | Mundipharma Korea | |
| 229 | 12 | 18 to 65 | Bulgaria, Serbia, Romania, Macedonia | Laboratoires SMB S.A. | |
| 108 | 12 | No details | Italy | Chiesi Farmaceutici S.p.A. | |
| 481a | 24 | 12 to 84 | Poland, Slovenia, Spain, Bulgaria, Czech Republic, Estonia, France, Germany, Hungary, Italy, Latvia, Lithuania, Belarus, Croatia, Romania, Russian Federation Ukraine | Chiesi Farmaceutici S.p.A. | |
| aThird arm not included. | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 All‐cause mortality Show forest plot | 15 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 Formoterol/budesonide vs salmeterol/fluticasone | 7 | 5935 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.03 [0.06, 16.44] |
| 1.1.2 Formoterol/beclomethasone vs salmeterol/fluticasone | 4 | 1257 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Not estimable |
| 1.1.3 Formoterol/mometasone vs salmeterol/fluticasone | 2 | 1126 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 4.46 [0.23, 85.40] |
| 1.1.4 Formoterol/fluticasone vs salmeterol/fluticasone | 2 | 270 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 7.39 [0.15, 372.38] |
| 1.2 All‐cause non‐fatal serious adverse events Show forest plot | 18 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 Formoterol/budesonide vs salmeterol/fluticasone | 7 | 5935 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.14 [0.82, 1.59] |
| 1.2.2 Formoterol/beclomethasone vs salmeterol/fluticasone | 6 | 1941 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.94 [0.43, 2.08] |
| 1.2.3 Formoterol/mometasone vs salmeterol/fluticasone | 2 | 1126 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.02 [0.47, 2.20] |
| 1.2.4 Formeterol/fluticasone vs salmeterol/fluticasone | 2 | 293 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.05 [0.00, 3.10] |
| 1.2.5 Formeterol/budesonide vs salmeterol/budesonide | 1 | 229 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 7.45 [0.15, 375.68] |
| 1.3 Asthma related non‐fatal serious adverse events Show forest plot | 16 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 Formoterol/budesonide vs salmeterol/fluticasone | 7 | 5935 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.69 [0.37, 1.26] |
| 1.3.2 Formoterol/beclomethasone vs salmeterol/fluticasone | 5 | 1510 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.01 [0.06, 16.24] |
| 1.3.3 Formoterol/mometasone v's salmeterol/fluticasone | 1 | 722 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 7.00 [0.14, 353.37] |
| 1.3.4 Formoterol/fluticasone vs salmeterol/fluticasone | 2 | 293 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.05 [0.00, 3.10] |
| 1.3.5 Formeterol/budesonide vs salmeterol/budesonide | 1 | 229 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 All‐cause mortality Show forest plot | 2 | 548 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Not estimable |
| 2.2 All‐cause non‐fatal serious adverse events Show forest plot | 2 | 548 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.72 [0.38, 19.46] |
| 2.3 Asthma related non‐fatal serious adverse events Show forest plot | 2 | 548 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Not estimable |
| 2.4 All‐cause non‐fatal serious adverse events Show forest plot | 2 | 548 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.72 [0.38, 19.46] |
| 2.4.1 Children | 2 | 548 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.72 [0.38, 19.46] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Busse SAE sensitivity analysis Show forest plot | 9 | 7061 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.08 [0.80, 1.46] |
| 3.2 Bernstein SAE sensitivity analysis Show forest plot | 2 | 1126 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.88 [0.43, 1.81] |
| 3.2.1 Formoterol/mometasone vs salmeterol/fluticasone | 2 | 1126 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.88 [0.43, 1.81] |
| 3.3 All‐cause non‐fatal SAE blinding Show forest plot | 11 | 6886 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.75, 1.46] |
| 3.3.1 Formoterol/budesonide vs salmeterol/fluticasone | 5 | 4663 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.72, 1.53] |
| 3.3.2 Formoterol/beclomethasone vs salmeterol/fluticasone | 5 | 1501 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.48, 2.59] |
| 3.3.3 Formoterol/mometasone vs salmeterol/fluticasone | 1 | 722 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.27, 3.29] |
| 3.4 Asthma‐related non‐fatal SAE blinding Show forest plot | 9 | 5733 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.40, 1.40] |
| 3.4.1 Formoterol/budesonide vs salmeterol/fluticasone | 5 | 4663 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.39, 1.40] |
| 3.4.2 Formoterol/beclomethasone vs salmeterol/fluticasone | 4 | 1070 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.06, 16.28] |
| 3.5 Single‐inhaler SAE sensitivity analysis Show forest plot | 8 | 6633 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.08 [0.80, 1.47] |
