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Combinación de bromuro de aclidinio y agonistas beta 2 de acción prolongada para la enfermedad pulmonar obstructiva crónica (EPOC)

Declaraciones de intereses de los autores

Versión publicada: 11 diciembre 2018 Historial de versiones

https://doi.org/10.1002/14651858.CD011594.pub2
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Resumen

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Antecedentes

Se aprobaron varias combinaciones de agonista beta2 de acción prolongada (ABAP) y de antagonista muscarínico de acción prolongada (AMAP) para el tratamiento de la enfermedad pulmonar obstructiva crónica (EPOC). Las recomendaciones GOLD actuales (Global Initiative for Chronic Obstructive Lung Disease) sugieren la administración de combinaciones de ABAP/AMAP en pacientes con: EPOC de grupo B con síntomas persistentes, EPOC de grupo C con exacerbaciones adicionales bajo tratamiento con AMAP solo y EPOC de grupo D con o sin corticosteroides inhalados (ICS). La combinación de dosis fija (CDF) de aclidinio/formoterol es uno de los tratamientos aprobados de ABAP/AMAP en pacientes con EPOC estable.

Objetivos

Evaluar la eficacia y la seguridad de la combinación de bromuro de aclidinio y agonistas beta2 de acción prolongada en la EPOC estable.

Métodos de búsqueda

Se realizaron búsquedas en el Registro Especializado del Grupo Cochrane de Vías Respiratorias (Cochrane Airways Group, [CAGR]), ClinicalTrials.gov, portal de ensayos de la Organización Mundial de la Salud (OMS), el portal de la Food and Drug Administration (FDA) de Estados Unidos y los sitios web del fabricante así como la lista de referencias de los ensayos publicados hasta el 12 de octubre de 2018.

Criterios de selección

Ensayos controlados aleatorios (ECA) de grupos paralelos que evaluaron el bromuro de aclidinio combinado con ABAP en pacientes con EPOC estable.

Obtención y análisis de los datos

Se usaron los procedimientos metodológicos estándar previstos por Cochrane para la recopilación y el análisis de datos. Los resultados primarios eran las exacerbaciones que requirieron un ciclo corto de un esteroide oral o de antibiótico, o ambos; calidad de vida medida con una escala validada y eventos adversos graves (EAG) no mortales. Cuando no se informó sobre los detalles de los resultados del estudio, se estableció contacto con los investigadores del estudio o con los coordinadores de ensayo de la compañía farmacéutica (o ambos) para obtener los datos que faltan.

Resultados principales

Se identificaron los ECA que compararon CDF de aclidinio/formoterol versus aclidinio, formoterol o placebo solo. Se incluyeron siete ensayos multicéntricos de cuatro a 52 semanas de duración realizados en contextos ambulatorios. Hubo 5921 participantes, cuya media de edad varió de 60,7 a 64,7 años, la mayoría eran hombres con una media de 46,4 a 61,3 paquetes de cigarrillos fumados por año; de estos, 43,9% a 63,4% eran fumadores activos. Tenían una EPOC de grado moderado a grave con un volumen espiratorio forzado en un segundo (VEM1) después del broncodilatador entre 50,5% y 61% del valor normal previsto y el valor medio inicial del VEM1 fue de 1,23 L a 1,43 L. Los sesgos de procedimiento y de detección de todos los estudios se calificaron como bajos, mientras que los sesgos de selección, de abandono y de notificación fueron bajos o inciertos.

CDF versus aclidinio

No hubo evidencia de una diferencia entre la CDF y aclidinio para las exacerbaciones que requirieron esteroides o antibióticos, o ambos (OR 0,95; IC del 95%: 0,71 a 1,27; dos ensayos, 2156 participantes; evidencia de certeza moderada); calidad de vida medida según la puntuación total del cuestionario George's Respiratory Questionnaire (SGRQ) (DM –0,92; IC del 95%: –2,15 a 0,30); participantes con mejoría significativa en la puntuación del SGRQ (OR 1,17; IC del 95%: 0,97 a 1,41; dos ensayos, 2002 participantes; evidencia de certeza moderada); EAG no mortal (OR 1,19; IC del 95%: 0,79 a 1,80; tres ensayos, 2473 participantes; evidencia de certeza moderada); ingresos hospitalarios debidos a exacerbaciones graves (OR 0,62; IC del 95%: 0,29 a 1,29; dos ensayos, 2156 participantes; evidencia de certeza moderada), o eventos adversos (OR 0,95; IC del 95%: 0,76 a 1,18; tres ensayos, 2473 participantes; evidencia de certeza moderada). En comparación con aclidinio, la CDF mejoró la puntuación focal de los síntomas (índice de disnea transitoria [TDI]: DM 0,37; IC del 95%: 0,07 a 0,68; dos ensayos, 2013 participantes) con mayor probabilidad de lograr una diferencia mínima clínicamente importante (DMCI) de al menos una unidad de mejoría (OR 1,34; IC del 95%: 1,11 a 1,62; evidencia de certeza alta); el número necesario a tratar para lograr un resultado beneficioso adicional [NNTB] es de 14 (IC del 95%: 9 a 39).

CDF versus formoterol

En comparación con el formoterol, el tratamiento combinado redujo las exacerbaciones que requirieron esteroides o antibióticos, o ambos (OR 0,78; IC del 95%: 0,62 a 0,99; tres ensayos, 2694 participantes; evidencia de certeza alta); puede disminuir la puntuación total del SGRQ (DM –1,88; IC del 95%: –3,10 a –0,65; dos ensayos, 2002 participantes; evidencia de certeza baja; La DMCI del SGRQ es de cuatro unidades); aumento de la puntuación focal del TDI (DM 0,42; IC del 95%: 0,11 a 0,72; dos ensayos, 2010 participantes) con más participantes que lograron una DMCI (OR 1,30; IC del 95%: 1,07 a 1,56; evidencia de certeza alta) y un NNTB de 16 (IC del 95%: 10 a 60). La CDF bajó el riesgo de eventos adversos en comparación con el formoterol (OR 0,78; IC del 95%: 0,65 a 0,93; cinco ensayos, 3140 participantes; evidencia de certeza alta; NNTB 22). Sin embargo, no hubo diferencias entre CDF y formoterol respecto de los ingresos hospitalarios, la mortalidad por todas las causas y los EAG no mortales.

CDF versus placebo

En comparación con placebo, la CDF no halló evidencia de una diferencia en las exacerbaciones que requirieron esteroides ni antibióticos, ni ambos (OR 0,82; IC del 95%: 0,60 a 1,12; dos ensayos, 1960 participantes; evidencia de certeza moderada) o ingresos hospitalarios debidos a exacerbaciones graves (OR 0,55; IC del 95%: 0,25 a 1,18; dos ensayos, 1960 participantes; evidencia de certeza moderada), aunque los cálculos fueron inciertos. La calidad de vida medida según la puntuación total del SGRQ mejoró significativamente con CDF en comparación con placebo (DM –2,91; IC del 95%: –4,33 a –1,50; dos ensayos, 1823 participantes), esto provocó un aumento correspondiente en la cantidad de pacientes que respondieron al SGRQ que lograron una disminución de al menos cuatro unidades en la puntuación total del SGRQ (OR 1,72; IC del 95%: 1,39 a 2,13; evidencia de certeza alta) con un NNTB de 7 (IC del 95%: 5 a 12). La CDF también mejoró los síntomas de la puntuación focal del TDI (DM 1,32; IC del 95%: 0,96 a 1,69; dos estudios, 1832 participantes) y más participantes lograron al menos una mejoría de una unidad en la puntuación focal del TDI (OR 2,51; IC del 95%: 2,02 a 3,11; evidencia de certeza alta; NNTB 4). No hubo diferencias en los EAG no mortales, ni en los eventos adversos, ni en la mortalidad por todas las causas entre CDF y placebo.

El tratamiento combinado mejoró significativamente el valor mínimo de la VEM1 en comparación con aclidinio, formoterol o placebo.

Conclusiones de los autores

La CDF mejoró la disnea y la función pulmonar en comparación con aclidinio, formoterol o placebo, lo que provocó un aumento de la cantidad de pacientes que respondieron con el tratamiento combinado. La calidad de vida mejoró con el tratamiento combinado en comparación con formoterol o con placebo. No hubo evidencia de una diferencia entre CDF y monoterapia o placebo para las exacerbaciones, los ingresos hospitalarios, la mortalidad, los EAG no mortales ni los eventos adversos. Los estudios informaron un riesgo menor de exacerbaciones moderadas y de eventos adversos con CDF en comparación con formoterol; sin embargo, los estudios más amplios producirían un cálculo más preciso para estos resultados.

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

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Los inhaladores con una combinación de bromuro de aclidinio y agonistas beta2 de acción prolongada, ¿son eficaces y seguros para los pacientes con EPOC estable?

Antecedentes

La enfermedad pulmonar obstructiva crónica (EPOC) es una afección de los pulmones que causa un estrechamiento de las vías respiratorias. Como resultado, los pacientes con EPOC presentan síntomas de disnea y tos, con producción de esputo, que empeoraron con el paso del tiempo. La causa principal es el tabaquismo o la inhalación de polvo. A los pacientes con EPOC, se les suele indicar inhaladores con medicamentos que expanden las vías respiratorias para aliviar los síntomas. Los medicamentos preferidos son los de acción prolongada que duran al menos medio día o un día. Este tipo de inhaladores son el aclidinio y el formoterol (un medicamento agonista beta2 de acción prolongada). Se intentó investigar cómo de eficaz resulta una combinación de aclidinio y agonista beta2 de acción prolongada en relación con el inhalador solo y el inhalador inactivo (placebo).

Características de los estudios

Solo se pudieron identificar los estudios con combinación de aclidinio y formoterol, y se incluyeron siete estudios con 5921 pacientes con EPOC de una duración de cuatro semanas a un año. La mayoría de los participantes eran hombres de unos 60 a 69 años, fumadores moderados o compulsivos, y aproximadamente la mitad de ellos eran fumadores activos. Cuando comenzaron el tratamiento presentaban síntomas moderados a graves de EPOC. Los pacientes de los estudios se trataron o bien con inhaladores combinados de aclidinio y formoterol, o con aclidinio, o formoterol, o placebo en un inhalador similar. Tanto los pacientes encargados de la investigación como los pacientes del estudio no sabían qué tratamiento recibían los participantes. Las conclusiones de esta revisión están actualizadas hasta octubre de 2018.

Resultados clave

Los pacientes tratados con el inhalador combinado y el inhalador con aclidinio no difirieron en cuanto a las exacerbaciones que requieren medicamentos adicionales, la calidad de vida y los efectos secundarios graves. Sin embargo, hubo menos casos de disnea que en quienes utilizaron un inhalador de aclidinio. 14 pacientes con EPOC deberían tratarse con inhaladores combinados para que un paciente más tenga una mejoría clínicamente significativa en la disnea.

Los pacientes con inhaladores combinados tienen menos probabilidades de presentar menos exacerbaciones, efectos secundarios y síntomas, así como una mejor calidad de vida en comparación con quienes usan un inhalador con formoterol. Pero, hubo una diferencia escasa o nula en los ingresos hospitalarios debidos a las exacerbaciones graves, los efectos secundarios graves o el riesgo de muerte.

En comparación con los inhaladores inactivos, los pacientes tratados con inhaladores combinados presentaron menos disnea y una mejor calidad de vida. Sería necesario tratar a siete pacientes con EPOC con inhalador combinado para lograr una mejoría importante en la calidad de vida que con un inhalador inactivo. Respecto de las exacerbaciones, los ingresos hospitalarios, los efectos secundarios graves y la muerte, no hubo diferencias entre lo inhaladores combinados y los inactivos.

Los pulmones funcionaron mejor en los pacientes con inhaladores combinados que en quienes utilizaron un inhalador inactivo o de un solo fármaco.

Calidad de la evidencia

Se debió interpretar los resultados con cautela, ya que todos los estudios incluidos fueron patrocinados por compañías farmacéuticas, y esto pudo haber generado sesgo. Sin embargo, los estudios incluidos en general se realizaron de una manera sistemática y aceptable. Tenemos la certeza de que los inhaladores combinados son más eficaces que los inhaladores inactivos o de un solo fármaco para la mejoría de la disnea y de la función pulmonar. Sin embargo, no se tuvo la misma certeza sobre los efectos en las exacerbaciones, los ingresos hospitalarios, la calidad de vida y los efectos secundarios.

Conclusión

Los inhaladores combinados son más eficaces que los inhaladores con un solo fármaco para aliviar la disnea y mejorar la función pulmonar. También producen una mejor calidad de vida en comparación con el formoterol o con los inhaladores inactivos. Sin embargo, no difieren respecto de los inhaladores inactivos o de un solo fármaco en cuanto a las exacerbaciones o los ingresos hospitalarios. Estos inhaladores combinados tienen perfiles de seguridad similares a los de los inhaladores inactivos o de un solo fármaco respecto de la muerte, los efectos secundarios o los efectos secundarios graves. Es probable que los inhaladores combinados hayan tenido menos efectos secundarios y exacerbaciones que el formoterol, pero se necesitan más estudios para respaldar este hallazgo con confianza. En resumen, los inhaladores combinados son una opción eficaz para el tratamiento de la EPOC y parecen tener un perfil de seguridad similar al de los inhaladores inactivos o de un solo fármaco.

Conclusiones de los autores

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Implicaciones para la práctica

El tratamiento combinado con aclidinio/formoterol proporciona mejorías en la función pulmonar y en la disnea en todas las comparaciones con aclidinio, formoterol o placebo, así como una mejor calidad de vida relacionada con la salud que el formoterol o el placebo. Sin embargo, todavía existe cierta falta de certeza sobre la superioridad respecto del aclidinio solo para la mejoría en la calidad de vida. Por lo tanto, el tratamiento combinado es un tratamiento adecuado para los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) confirmada y estable. La evidencia actual no es suficiente para confirmar los efectos de la combinación aclidinio/formoterol en las probabilidades de presentar una exacerbación o ingresos hospitalarios debidos a las exacerbaciones. Como no hay evidencia de una diferencia en la mortalidad ni en los eventos adversos graves no mortales en comparación con las monoterapias ni con el placebo, la combinación de dosis fija de aclidinio/formoterol podría considerarse una opción relativamente segura para tratar a los pacientes con EPOC estable.

Implicaciones para la investigación

Se necesitan estudios de investigación adicionales para esclarecer las posibles diferencias en la eficacia entre aclidinio/formoterol y las combinaciones alternativas de ABAP/AMAP, en particular respecto a la calidad de vida, la disnea y las exacerbaciones. Los investigadores deben definir e informar sobre las exacerbaciones de manera sistemática y, si fuera posible, proporcionar datos desglosados por participantes en diferentes grupos de gravedad de la EPOC. Los datos de seguimiento a más largo plazo resultarían beneficiosos, especialmente para identificar cualquier tipo de efecto de la combinación aclidinio/formoterol en las exacerbaciones, los ingresos hospitalarios, los eventos adversos graves y la mortalidad. Resultaría más apropiado contar con ensayos adicionales que analicen la eficacia y la seguridad de aclidinio/formoterol de los resultados relacionados con el participante como medida de resultado primario, en lugar de la mejoría de la función pulmonar, para la aplicabilidad en la práctica clínica en pacientes con EPOC. También se prevén estudios sobre la coste‐efectividad que comparen aclidinio/formoterol con otras combinaciones disponibles de ABAP/AMAP.

Summary of findings

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Summary of findings for the main comparison. Fixed‐dose combination aclidinium/formoterol compared to aclidinium alone for chronic obstructive pulmonary disease (COPD)

Fixed‐dose combination aclidinium/formoterol compared to aclidinium for chronic obstructive pulmonary disease (COPD)

Patient or population: people with COPD
Setting: community
Intervention: FDC aclidinium/formoterol
Comparison: aclidinium

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with aclidinium

Risk with FDC aclidinium/formoterol

Exacerbations requiring steroids or antibiotics or both: number of participants
Follow‐up: 24 weeks

105 per 1000

101 per 1000
(77 to 130)

OR 0.95
(0.71 to 1.27)

2156
(2 RCTs)

⊕⊕⊕⊝
Moderatea

—

Quality of life: number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score
Follow‐up: 24 weeks

541 per 1000

579 per 1000
(533 to 624)

OR 1.17
(0.97 to 1.41)

2002
(2 RCTs)

⊕⊕⊕⊝
Moderatea

The mean quality of life: change from baseline in SGRQ total score was 0.92 lower (2.15 lower to 0.3 higher) in FDC group (2002 participants, 2 RCTs)

Non‐fatal serious adverse events
Follow‐up: 4–24 weeks

41 per 1000

49 per 1000
(33 to 72)

OR 1.19
(0.79 to 1.80)

2473
(3 RCTs)

⊕⊕⊕⊝
Moderatea

—

Hospital admissions due to exacerbations: number of participants
Follow‐up: 24 weeks

18 per 1000

11 per 1000
(5 to 23)

OR 0.62
(0.29 to 1.29)

2156
(2 RCTs)

⊕⊕⊕⊝
Moderatea

—

Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit)
Follow‐up: 24 weeks

557 per 1000

627 per 1000
(582 to 671)

OR 1.34
(1.11 to 1.62)

2013
(2 RCTs)

⊕⊕⊕⊕
High

The mean improvement in symptoms: change from baseline in TDI focal score was 0.37 higher (0.07 higher to 0.68 higher) in FDC group (2013 participants, 2 RCTs).

Change in lung function: from baseline in trough FEV1 (L)
Follow‐up: 4–24 weeks

Mean change from baseline in trough FEV1 (L) across aclidinium group ranged from –0.017 to 0.066

Mean change from baseline in trough FEV1 (L) in the FDC group was 0.02 higher (0 to 0.04 higher)

—

2333
(3 RCTs)

⊕⊕⊕⊕
High

—

Adverse events (not including serious adverse events): number of participants

Follow‐up: 4–24 weeks

194 per 1000

186 per 1000
(155 to 221)

OR 0.95
(0.76 to 1.18)

2473
(3 RCTs)

⊕⊕⊕⊝
Moderatea

—

*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).

CI: confidence interval; COPD: chronic obstructive pulmonary disease; FDC: fixed‐dose combination; FEV1: forced expiratory volume in 1 second; OR: odds ratio; RCT: randomised controlled trial; SGRQ: St George's Respiratory Questionnaire; TDI: Transitional Dyspnoea Index.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for serious imprecision: the CIs included a potential for appreciable benefit or harm.

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Summary of findings 2. Fixed‐dose combination aclidinium/formoterol compared to formoterol for chronic obstructive pulmonary disease (COPD)

Fixed‐dose combination aclidinium/ formoterol compared to formoterol for chronic obstructive pulmonary disease (COPD)

Patient or population: people with COPD
Setting: community
Intervention: FDC aclidinium/formoterol
Comparison: formoterol

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with formoterol

Risk with FDC aclidinium/formoterol

Exacerbations requiring steroids or antibiotics or both: number of participants
Follow‐up: 24 weeks

154 per 1000

124 per 1000
(101 to 152)

OR 0.78
(0.62 to 0.99)

2694
(3 RCTs)

⊕⊕⊕⊕
High

—

Quality of life: number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score
Follow‐up: 24 weeks

524 per 1000

559 per 1000
(495 to 623)

OR 1.15
(0.89 to 1.50)

1000
(1 RCT)

⊕⊕⊝⊝
Lowa,b

The mean quality of life: change from baseline in SGRQ total score was 1.88 lower (3.1 lower to 0.65 lower) in FDC group (2002 participants, 2 RCTs).

Non‐fatal serious adverse events
Follow‐up: 4–52 weeks

50 per 1000

58 per 1000
(42 to 79)

OR 1.15
(0.82 to 1.61)

3140
(5 RCTs)

⊕⊕⊕⊝
Moderatea

—

Hospital admissions due to exacerbations: number of participants
Follow‐up: 24–52 weeks

27 per 1000

20 per 1000
(12 to 34)

OR 0.76
(0.45 to 1.28)

2694
(3 RCTs)

⊕⊕⊕⊝
Moderatea

—

Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit)
Follow‐up: 24 weeks

565 per 1000

628 per 1000
(582 to 670)

OR 1.30
(1.07 to 1.56)

2010
(2 RCTs)

⊕⊕⊕⊕
High

The mean improvement in symptoms: change from baseline in TDI focal score was 0.42 higher (0.11 higher to 0.72 higher) in FDC group (2010 participants, 2 RCTs).

Change in lung function: from baseline in trough FEV1 (L)
Follow‐up: 4–24 weeks

Mean change from baseline in trough FEV1 (L) across formoterol group ranged from –0.002 to 0.118

Mean change from baseline in trough FEV1 (L) in the FDC group was 0.04 higher (0.03 higher to 0.06 higher)

—

2411
(4 RCTs)

⊕⊕⊕⊕
High

—

Adverse events (not including serious adverse events): number of participants
Follow‐up: 4–52 weeks

271 per 1000

225 per 1000
(195 to 257)

OR 0.78
(0.65 to 0.93)

3140
(5 RCTs)

⊕⊕⊕⊕
High

—

*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).

CI: confidence interval; COPD: chronic obstructive pulmonary disease; FDC: fixed‐dose combination; FEV1: forced expiratory volume in 1 second; OR: odds ratio; RCT: randomised controlled trial; SGRQ: St George's Respiratory Questionnaire; TDI: Transitional Dyspnoea Index.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for serious imprecision: CIs included a potential for appreciable benefit or harm.

bDowngraded one level as ACLIFORM COPD did not report the SGRQ responders for formoterol arm in the published articles.

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Summary of findings 3. Fixed‐dose combination aclidinium/formoterol compared to placebo for chronic obstructive pulmonary disease (COPD)

Fixed dose combination aclidinium/formoterol compared to placebo for chronic obstructive pulmonary disease (COPD)

Patient or population: people with chronic obstructive pulmonary disease (COPD)
Setting: community
Intervention: FDC aclidinium/formoterol
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with FDC aclidinium/formoterol

Exacerbations requiring steroids or antibiotics or both: number of participants
Follow‐up: 24 weeks

129 per 1000

109 per 1000
(82 to 143)

OR 0.82
(0.60 to 1.12)

1960
(2 RCTs)

⊕⊕⊕⊝
Moderatea

—

Quality of life: number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score
Follow‐up: 24 weeks

433 per 1000

568 per 1000
(515 to 619)

OR 1.72
(1.39 to 2.13)

1823
(2 RCTs)

⊕⊕⊕⊕
High

The mean quality of life: change from baseline in SGRQ total score was 2.91 lower (4.33 lower to 1.5 lower) in FDC group (1823 participants, 2 RCTs).

Non‐fatal serious adverse events
Follow‐up: 4–24 weeks

38 per 1000

42 per 1000
(27 to 64)

OR 1.12
(0.72 to 1.74)

2527
(4 RCTs)

⊕⊕⊕⊝
Moderatea

—

Hospital admissions due to exacerbations: number of participants
Follow‐up: 24 weeks

21 per 1000

12 per 1000
(5 to 25)

OR 0.55
(0.25 to 1.18)

1960
(2 RCTs)

⊕⊕⊕⊝
Moderatea

—

Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit)
Follow‐up: 24 weeks

394 per 1000

620 per 1000
(568 to 669)

OR 2.51
(2.02 to 3.11)

1832
(2 RCTs)

⊕⊕⊕⊕
High

The mean improvement in symptoms: change from baseline in TDI focal score was 1.32 higher (0.96 higher to 1.69 higher) in FDC group (1832 participants, 2 RCTs).

Change in lung function: from baseline in trough FEV1 (L)
Follow‐up: 4–24 weeks

Mean change from baseline in trough FEV1 (L) across placebo group ranged from –0.061 to –0.031

Mean change from baseline in trough FEV1 (L) in the FDC group was 0.12 higher (0.10 higher to 0.14 higher)

—

2137
(3 RCTs)

⊕⊕⊕⊕
High

—

Adverse events (not including serious adverse events): number of participants
Follow‐up: 4–24 weeks

175 per 1000

171 per 1000
(139 to 206)

OR 0.97
(0.76 to 1.22)

2527
(4 RCTs)

⊕⊕⊕⊝
Moderatea

—

*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).

CI: confidence interval; COPD: chronic obstructive pulmonary disease; FDC: fixed‐dose combination; FEV1: forced expiratory volume in 1 second; OR: odds ratio; RCT: randomised controlled trial; SGRQ: St George's Respiratory Questionnaire; TDI: Transitional Dyspnoea Index.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for serious imprecision: the CIs included a potential for appreciable benefit or harm.

Antecedentes

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Descripción de la afección

La enfermedad pulmonar obstructiva crónica (EPOC) se caracteriza por una limitación lentamente progresiva en el flujo aéreo, que no se puede revertir por completo, y se asocia con una mejor respuesta inflamatoria en las vías respiratorias y destrucción del parénquima pulmonar (Barnes 2000; Criner 2015; GOLD 2018). Es la cuarta causa principal de muerte en Canadá y la tercera en los EE.UU., se estimó que 12,7 millones de adultos en los EE.UU. presentaban EPOC en 2011 (Criner 2015). Como resultado de una exposición continua al tabaco y a la contaminación ambiental, se prevé que para 2020 la EPOC sea la tercera causa principal de muerte en todo el mundo(Chapman 2006; GOLD 2018; Raherison 2009). Una prevalencia de la EPOC bien descrita de aproximadamente 15% en fumadores se considera una subestimación debida al infradiagnóstico (Rennard 2006), y se observa que alcanza hasta un 50% en los fumadores compulsivos, según los criterios actuales (Mannino 2007). El tabaquismo activo sigue siendo el principal factor de riesgo de EPOC, lo que plantea una amenaza grave para la salud en más de 1100 millones de fumadores en todo el mundo (Bauer 2013). Sin embargo, los no fumadores también se ven afectados por la EPOC, con una prevalencia de 3% a 11% informada en las personas que nunca fumaron (GOLD 2018). En un estudio poblacional de personas que nunca fumaron en la vida, el riesgo de EPOC se asoció, de forma independiente, con el tabaquismo pasivo o el humo de tabaco en el ambiente (Hagstad 2014). Otros factores, como la exposición a los combustibles de biomasa y la contaminación del aire en ambientes cerrados, son causas importantes de EPOC en países de ingresos bajos a medios (Bruce 2000; Rivera 2008).

La limitación crónica del flujo aéreo en la EPOC es provocada por una mezcla de enfermedades de las pequeñas vías respiratorias (bronquiolitis obstructiva) y destrucción del parénquima (enfisema)(GOLD 2018). La destrucción de los alvéolos y del parénquima pulmonar por infiltrados inflamatorios provoca un aumento del volumen de los espacios aéreos y, por lo tanto, se reduce la presión elástica que genera el flujo espiratorio (Cosio 2009; GOLD 2018) La aparición de síntomas suele ocurrir cuando el volumen espiratorio forzado en un segundo (VEM1) disminuya a aproximadamente el 50% del valor normal previsto (Sutherland 2004).

Las exacerbaciones de la EPOC son una causa importante de morbilidad y de mortalidad; una exacerbación se define como "un evento agudo caracterizado por un empeoramiento de los síntomas respiratorios del paciente que supera las variaciones diarias normales y que motiva un cambio en la medicación" (GOLD 2018). Las infecciones respiratorias virales y bacterianas son los principales detonantes de las exacerbaciones que se asocian con un empeoramiento de la calidad de vida, mayores costes sanitarios, disminución acelerada de la función pulmonar y disminución de la supervivencia (Bauer 2013; Marchetti 2013; Mullerova 2015). Las exacerbaciones pueden presentarse en cualquier etapa de la EPOC; sin embargo, la frecuencia de las exacerbaciones se correlaciona con la gravedad de la limitación del flujo aéreo, con una tasa media de 1,34 eventos/año en pacientes en estadio 3 de la enfermedad según la clasificación GOLD (Global Initiative for Chronic Obstructive Lung Disease) y 2,00 eventos/año en pacientes en estadio 4 de la enfermedad según la clasificación GOLD (Marchetti 2013). Un estudio observacional prospectivo de tres años con 2138 participantes informó sobre las exacerbaciones graves que requirieron el ingreso hospitalario en alrededor de 30% de los participantes, y esto se traduce en una carga económica significativa (Mullerova 2015). El pronóstico a largo plazo de los pacientes con hospitalizaciones relacionadas con las exacerbaciones es deficiente, con tasas de mortalidad de 26% a los dos años y de 55% a los cinco años(Marchetti 2013; Mullerova 2015)

Los objetivos principales del tratamiento en la EPOC estable son los siguientes: aliviar los síntomas, reducir las exacerbaciones y mejorar la calidad de vida y la tolerancia al ejercicio (ATS/ERS 2011; GOLD 2018; Sutherland 2004 TSANZ 2018) Los broncodilatadores son la base para el tratamiento sintomático de la EPOC estable (Tashkin 2004); broncodilatadores inhalados de acción prolongada (tanto los agonistas beta2 como los anticolinérgicos) son más eficaces que los broncodilatadores de acción corta para mantener el alivio de los síntomas (GOLD 2018). Cierta evidencia indica que la iniciación precoz del tratamiento con broncodilatadores de acción prolongada, en los casos leves a moderados de la EPOC estable, puede afectar la disminución de la función pulmonar y la calidad de vida relacionada con la salud (CdVRS)(Welte 2015). Sin embargo, los corticosteroides inhalados (ICS) en la enfermedad precoz no tienen ningún efecto en la función pulmonar (Welte 2015), y la monoterapia a largo plazo no se recomienda para la EPOC estable (GOLD 2018). Los ICS se indican como tratamiento a largo plazo solamente para los pacientes con limitación del flujo aéreo grave a muy grave que presentan exacerbaciones frecuentes, a pesar del uso de broncodilatadores de acción prolongada (GOLD 2018; TSANZ 2018). Las guías actuales recomiendan el tratamiento combinado con agonistas inhalados beta2 de acción prolongada (ABAP) y antagonistas muscarínicos de acción prolongada (AMAP) como opción terapéutica para los pacientes con EPOC estable moderada a grave, si no se observan mejorías en los síntomas con el consumo de un único agente (GOLD 2018). Como consecuencia de mecanismos complementarios e independientes para la broncodilatación, el tratamiento combinado de AMAP/ABAP proporciona una mejoría significativamente mayor en la función pulmonar en comparación con la monoterapia con AMAP o ABAP en pacientes con EPOC moderada a grave (Cazzola 2010; Tashkin 2008; van der Molen 2012); sin embargo, el efecto en los resultados informados por el paciente son limitados (GOLD 2018).

Descripción de la intervención

Bromuro de aclidinio

El bromuro de aclidinio es un anticolinérgico de acción prolongada que bloquea la acción del neurotransmisor acetilcolina. Tiene efectos antagonistas potentes en todos los subtipos de receptores muscarínicos de acetilcolina (M1 a M5)(Ulrik 2012); sin embargo, solo los subtipos M2 y M3 están presentes en el músculo liso de las vías respiratorias(Moulton 2011). La broncoconstricción inducida por acetilcolina está mediada principalmente por los receptores M3 e indirectamente por los receptores M2, que previenen la relajación bronquial mediada por el receptor adrenérgico beta2 a través de la inhibición de la adenilato‐ciclasa (Moulton 2011). Los receptores M2 también median la inhibición por retroalimentación de la liberación de acetilcolina en las terminaciones nerviosas colinérgicas (Karakiulakis 2012; Sims 2011). El aclidinio se disocia del receptor M3 en forma más lenta que del receptor M2, porque tiene una selectividad cinética seis veces mayor para el subtipo M3 en comparación con el M2, esto genera una acción broncodilatadora más eficaz con menos efectos adversos cardíacos mediados por M2 (Maltais 2012; Sims 2011).

El aclidinio se aprobó como tratamiento de mantenimiento de dos dosis diarias para la EPOC estable (FDA 2012). En una revisión Cochrane (Ni 2014), el aclidinio redujo la cantidad de participantes con hospitalizaciones relacionadas con las exacerbaciones, en comparación con el placebo (odds ratio [OR] 0,64; intervalo de confianza (IC) del 95%: 0,46 a 0,88). Dentro de la propia revisión, el aclidinio también se asoció con un beneficio significativo respecto del placebo en la CdVRS, la disnea y los índices de la función pulmonar. El aclidinio no produjo reducciones significativas en las exacerbaciones que requirieron un ciclo corto de un esteroide oral o antibiótico, o ambos. Sin embargo, no hubo evidencia sólida para respaldar la superioridad del aclidinio sobre el estándar actual de atención, tiotropio o ABAP (Ni 2014).

Agonistas β2 de acción prolongada

Los ABAP inhalados son de uso difundido como tratamiento de mantenimiento en pacientes con EPOC con limitación del flujo aéreo moderado a grave y como tratamiento alternativo para pacientes con enfermedad leve (GOLD 2018). Desde fines de los años noventa, se ha usado el salmeterol y el formoterol dos veces al día en la práctica clínica. Para mejorar el cumplimiento están disponibles preparaciones diarias de ABAP que tienen una duración aún mayor (Zafar 2014). El indacaterol es el primer ABAP de toma diaria autorizado para uso clínico por la Food and Drug Administration (FDA) de los EE.UU. y se aprobó en julio de 2011 (FDA 2011). Esto fue seguido de aprobaciones de preparaciones combinadas de ABAP una vez al día con ICS o AMAP. La FDA aprobó la combinación de vilanterol–fluticasona en mayo de 2013 (FDA 2013a) y la combinación vilanterol–umeclidinio en diciembre de 2013 (FDA 2013b), como tratamiento de mantenimiento a largo plazo, una vez al día, en pacientes con EPOC estable.

Los receptores beta2 se localizan principalmente en el músculo liso bronquial, pero los receptores beta1 se localizan mayormente en el corazón. Sin embargo, los receptores beta2 del corazón dan cuenta del 10% al 50% de la cantidad total de receptores beta del corazón, y esto se traduce en la probabilidad de efectos adversos cardíacos, incluso con agonistas beta2 muy selectivos (Karner 2012). Todos los agonistas inhalados beta2 provocan broncodilatación mediante una cascada de reacciones y activación de los receptores beta2 en las células del músculo liso de las vías respiratorias, que varían en los mecanismos de acción exactos en los diferentes ABAP (Kew 2013) EL formoterol es un ABAP muy selectivo de acción rápida con escasa afinidad por los receptores beta1 y por los receptores adrenérgicos alfa que causan relajación bronquial mediante la liberación progresiva desde el depósito en la membrana plasmática para interactuar con el sitio activo del receptor beta2 (Berger 2008; Johnson 1998). El salmeterol tiene un inicio de acción más lento que el formoterol, a través del cual la cadena lateral del salmeterol se une al receptor adrenérgico beta2, pero la cabeza se une y se libera en forma continua del sitio activo del receptor (Johnson 1998; Karner 2012) El indacaterol tiene un inicio de acción rápido de menos de cinco minutos (Zafar 2014), y la afinidad por los dominios lipídicos dentro de la membrana es mayor que el salmeterol, lo que genera una mayor duración de la acción (Beier 2011; Karner 2012). Un estudio exploratorio desenmascarado de corto plazo halló que el indacaterol produjo una mejoría significativamente mayor en la capacidad inspiratoria(Beier 2009).

Las pautas actuales respaldan los ABAP como el tratamiento de primera línea para pacientes con EPOC estable, ya que reducen las exacerbaciones, incluso en quienes requieren hospitalizaciones, y al mismo tiempo mejoran la calidad de vida y la función pulmonar (Kew 2013). La incorporación de un tratamiento regular con ICS solo se recomienda para los pacientes con exacerbaciones frecuentes (GOLD 2018; Spencer 2011). El tratamiento combinado de ABAP/ICS en un mismo inhalador se asocia con una reducción en las exacerbaciones en comparación con placebo, ABAP solo o ICS solo; sin embargo, aumenta el riesgo de neumonía (Nannini 2012; Nannini 2013a; Nannini 2013b). En comparación con el tiotropio, los ABAP tienen una eficacia similar en la mejoría de los síntomas (Appleton 2006; Chong 2012).

Los efectos adversos informados de ABAP incluyen los eventos cardíacos como las arritmias, la insuficiencia cardíaca y el síndrome coronario agudo; temblores; tos; sequedad bucal y cefalea (Berger 2008; Gershon 2013), así como un posible mayor riesgo de muerte cardiovascular, especialmente en los pacientes con asma (Hanania 2013). Sin embargo, no hay evidencia sólida que indique diferencias significativas en la mortalidad ni en las complicaciones cardiovasculares entre el salmeterol o el formoterol y el placebo en pacientes con EPOC (Ferguson 2003; Rodrigo 2008)

De qué manera podría funcionar la intervención

Los ABAP y el aclidinio producen una relajación del músculo liso a través de dos vías diferentes: sistemas simpático (ABAP) y parasimpático (aclidinio). Se propuso que la actividad del sistema simpático es más importante durante el día, mientras que el sistema parasimpático desempeña una función más importante durante la noche (Cazzola 2010). Una combinación de ambos fármacos tiene la capacidad de aumentar la broncodilatación y superar la variabilidad entre pacientes e intra‐pacientes del tono broncomotor asociado con EPOC (Cazzola 2010; de Miguel‐Diez 2014; Tashkin 2013). Se informó sobre la actividad cruzada de la acetilcolina en el sistema simpático y de las catecolaminas adrenérgicas en el sistema parasimpático en modelos preclínicos (Matera 2014). Se sabe que la broncoconstricción mediada por acetilcolina ocurre principalmente a través de los receptores muscarínicos del subtipo M3 y también es regulada por receptores beta2 adrenérgicos antes de la unión (Tashkin 2013). Incluso, un aumento en el monofosfato de adenosina cíclico (AMPc) mediado por el receptor beta, que causa relajación del músculo liso bronquial, también es afectado por los receptores M2 que se oponen funcionalmente acoplándose con adenilato‐ciclasa a través de una proteína G inhibitoria(Matera 2014).

Cuando se utiliza el tratamiento combinado de ABAP/AMAP, la broncodilatación se logra tanto por vía directa como indirecta. La combinación de ABAP con aclidinio amplifica la acción de aclidinio mediante la modulación de la neurotransmisión colinérgica por receptores beta2 adrenérgicos, además de la estimulación directa de los receptores beta2 adrenérgicos en el músculo liso (Cazzola 2013; van der Molen 2012). Asimismo, el aclidinio aumenta la relajación bronquial estimulada por agonistas beta2 por la disminución de los efectos broncoconstrictores de la acetilcolina (Tashkin 2013). Por lo tanto, la combinación de bromuro de aclidinio y ABAP se espera que produzca una broncodilatación más eficaz que la producida por los componentes individuales aislados.

Por qué es importante realizar esta revisión

GOLD 2018 sugiere la administración del tratamiento dual AMAP/ABAP como una opción de tratamiento para los pacientes en los grupos B según la GOLD (síntomas altos/riesgo bajo), C (síntomas bajos/riesgo alto) y D (síntomas altos/riesgo alto). Los datos de los ensayos sobre los tratamientos combinados de ABAP/AMAP con un ABAP bien establecido, el tiotropio, demostraron una mejoría mayor en los resultados centrados en el paciente (por ejemplo: disnea, síntomas, uso de medicación de rescate y CdVRS) en comparación con la observada con los fármacos individuales solos (van der Molen 2012). Una revisión Cochrane informó una leve mejoría de importancia clínica en la CdVRS con la combinación de ABAP y tiotropio en comparación con tiotropio solo en pacientes con EPOC moderada a grave (Karner 2012).

El aclidinio se aprobó en 2012 para su administración en pacientes con EPOC moderada a grave; una cantidad importante de ensayos controlados aleatorios (ECA) investigó los riesgos y los beneficios de la combinación de bromuro de aclidinio y ABAP en comparación con placebo o con tratamientos inhalados individuales. Sin embargo, tanto para los pacientes como los médicos que se enfrentan a pacientes, aún no hay una respuesta para la pregunta sobre la eficacia y la seguridad de esta combinación; por lo tanto, nuestro objetivo fue salvar esta brecha de evidencia con la presente revisión.

Objetivos

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Evaluar la eficacia y la seguridad de la combinación de bromuro de aclidinio y agonistas beta2 de acción prolongada en la EPOC estable.

Métodos

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Criterios de inclusión de estudios para esta revisión

Tipos de estudios

Se incluyeron los ECA de diseño de grupo paralelo. Se incluyeron ensayos tanto abiertos como cegados. Se excluyeron los ensayos cruzados y los asignados al azar por grupo.

Tipos de participantes

Se incluyeron a adultos de 18 años de edad o más con diagnóstico de EPOC según los criterios GOLD (GOLD 2018), la American Thoracic Society (ATS), la European Respiratory Society (ERS) (ATS/ERS 2011), la Thoracic Society of Australia and New Zealand (TSANZ) (TSANZ 2018), el UK National Institute for Health and Care Excellence (NICE 2010), o la Organización Mundial de la Salud (OMS). Los participantes tenían indicios de obstrucción en las vías respiratorias (relación entre volumen espiratorio forzado en un segundo después del broncodilatador ([VEM1]/capacidad vital forzada [CVF] menor que 70%) con síntomas de disnea, tos crónica o producción de esputo con o sin antecedentes de tabaquismo. Se excluyeron los estudios que inscribieron a participantes con asma bronquial, bronquiectasia, fibrosis quística u otras enfermedades pulmonares crónicas.

Tipos de intervenciones

Se incluyeron ensayos que compararon bromuro de aclidinio/ABAP versus placebo, bromuro de aclidinio, ABAP o AMAP. ABAP y AMAP debían integrar los tratamientos asignados al azar de los estudios incluidos. La duración mínima de los ensayos fue de cuatro semanas. Se planificó estudiar las siguientes comparaciones.

  • Combinación libre de bromuro de aclidinio/ABAP en inhaladores independientes:

    • versus bromuro de aclidinio;

    • versus el mismo ABAP;

    • versus AMAP; o

    • versus placebo.

  • Combinación de dosis fija (CDF) de bromuro de aclidinio/ABAP en un inhalador:

    • versus bromuro de aclidinio;

    • versus el mismo ABAP;

    • versus AMAP; o

    • versus placebo.

Se incluyeron las siguientes cointervenciones siempre que no formen parte del tratamiento asignado al azar: salbutamol o albuterol como medicación de rescate, teofilina oral de liberación lenta, ICS o corticosteroides sistémicos (orales o parenterales) en dosis estables y oxigenoterapia menor a 15 horas/día.

Tipos de medida de resultado

Resultados primarios

  • Exacerbaciones que requirieron un ciclo corto de un esteroide oral o de antibióticos, o de ambos;

  • Calidad de vida según una escala validada, St George's Respiratory Questionnaire (SGRQ) o la Chronic Respiratory Diseases Questionnaire (CRQ).

  • Eventos adversos graves (EAG) no mortales; por ejemplo, cualquier evento adverso potencialmente mortal o que ponga al participante en riesgo inmediato de muerte; requiere la hospitalización del paciente o bien la prolonga; provoca discapacidad/incapacidad persistente o significativa (es decir, una interrupción apreciable en la capacidad del individuo para realizar funciones vitales normales); provoca malformaciones congénitas o defectos de nacimiento; u otras afecciones de importancia clínica que los investigadores consideraron que representaban riesgos importantes

Resultados secundarios

  • Mortalidad (respiratoria y por todas las causas).

  • Ingresos hospitalarios debidos a las exacerbaciones.

  • La mejoría en los síntomas según el índice de disnea transitoria (TDI).

  • Cambio en la función pulmonar.

  • Eventos adversos que no incluyen los EAG.

El informe en el ensayo de uno o más de los resultados mencionados aquí no fue un criterio de inclusión para la revisión.

Métodos de búsqueda para la identificación de los estudios

Búsquedas electrónicas

We searched the Cochrane Airways Trials Register up to 12 October 2018 with no restrictions on language or type of publication. The Cochrane Airways Trials Register is maintained by the information specialist for Cochrane Airways and contains studies identified from the following sources:

  • monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL), through the Cochrane Register of Studies (CRS);

  • weekly searches of MEDLINE Ovid;

  • weekly searches of Embase Ovid;

  • monthly searches of PsycINFO Ovid;

  • monthly searches of CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature);

  • monthly searches of AMED EBSCO (Allied and Complementary Medicine);

  • handsearches of the proceedings of major respiratory conferences.

Studies contained in the Trials Register are identified through search strategies based on the scope of Cochrane Airways. Details of these strategies, as well as a list of handsearched conference proceedings are in Appendix 1. See Appendix 2 for search terms used to identify studies for this review.

We also conducted a search of www.ClinicalTrials.gov (Appendix 3) and the WHO trials portal (WHO ICTRP) up to 12 October 2018.

Búsqueda de otros recursos

We checked reference lists of all primary studies and review articles for additional references. We searched relevant manufacturers' websites (Forest Pharmaceuticals, Almirall, and AstraZeneca) and the US FDA website (FDA) for trial information. We also searched for errata or retractions from included studies published as full‐text articles on PubMed and reported within the review the date this was done. We planned to translate trials published in a language other than English. The date of the last search was 12 October 2018.

Obtención y análisis de los datos

Selección de los estudios

Two review authors (HN and KTM) independently screened titles and abstracts for inclusion of all potential studies identified as a result of the search and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve.' Two review authors (SM and KTM) independently screened the full‐text articles, identified studies for inclusion, and identified and recorded reasons for exclusion of ineligible studies. We resolved disagreements through discussion, or, if required, we consulted a third review author (ZS). We identified and excluded duplicates and collated multiple reports of the same study, so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram and a Characteristics of excluded studies table.

Extracción y manejo de los datos

We used a data collection form that was piloted on at least one study in the review to document study characteristics and outcome data. One review author (SM) extracted the following characteristics from included studies.

  • Methods: study design, total duration of study, details of any 'run‐in' period, number of study centres and locations, study setting, withdrawals and date of study.

  • Participants: number, mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria and exclusion criteria.

  • Interventions: intervention, comparison, concomitant medications and excluded medications.

  • Outcomes: primary and secondary outcomes specified and collected and time points reported.

  • Notes: funding for trial and notable conflicts of interest of trial authors.

Two review authors (HN and KTM) independently extracted outcome data from included studies. We noted in the Characteristics of included studies table if outcome data were not reported in a usable way. We resolved disagreements by consensus or by consultation with a third review author (KNV). One review author (HN) transferred data into Review Manager 5 (Review Manager 2014). We double‐checked that data were entered correctly by comparing the data presented in the systematic review versus those provided in the study reports. A second review author (KTM) spot‐checked study characteristics for accuracy against those provided in the trial report.

Evaluación del riesgo de sesgo de los estudios incluidos

Two review authors (HN and SM) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved disagreements by discussion or by consultation with another review author (ZS). We assessed risk of bias according to the following domains.

  • Random sequence generation.

  • Allocation concealment.

  • Blinding of participants and personnel.

  • Blinding of outcome assessment.

  • Incomplete outcome data.

  • Selective outcome reporting.

  • Other bias.

We graded each potential source of bias as high, low or unclear and provided a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We summarised risk of bias judgements across different studies for each of the domains listed. We considered blinding separately for different key outcomes when necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a participant‐reported pain scale). When information on risk of bias related to unpublished data or correspondence with a trialist, we noted this in the 'Risk of bias' table.

When considering treatment effects, we took into account risk of bias for the studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We conducted the review according to the published protocol and reported deviations from it in the Differences between protocol and review section of the systematic review.

Medidas del efecto del tratamiento

We analysed dichotomous data as odds ratios (OR), and continuous data as mean differences (MD) if studies used the same measurement scale or standardised mean differences (SMD) if studies used different scale measurements, with 95% confidence intervals (CI). We entered data presented as a scale with a consistent direction of effect. We applied Peto OR, with 95% CI for rare events.

We undertook meta‐analyses only when this was meaningful (i.e. if treatments, participants and the underlying clinical question were similar enough for pooling to make sense). We narratively described skewed data reported as medians and interquartile ranges. When multiple trial arms were reported in a single trial, we included only the relevant arms in the analysis and reported the other treatment arms in the Characteristics of included studies table. When two comparisons (e.g. drug A versus placebo and drug B versus placebo) were combined in the same meta‐analysis, we halved the control group to avoid double‐counting.

Cuestiones relativas a la unidad de análisis

We analysed the number of participants instead of the number of events for outcomes that may have occurred more than once, such as exacerbations, hospital admissions and adverse events. For exacerbation rates, we planned to analyse the data as rate ratios, transformed them into log rate ratios and combined them across studies using the generic inverse variance method.

To prevent unit of analysis error In studies with multiple intervention arms, for dichotomous data, we divided up both the number of participants and the number of events according to the number of interventions in the study. For continuous data, we only divided the total number of participants and the means and standard deviations remained unchanged. If we needed to combine groups, we summed both sample sizes and the numbers of people with events for dichotomous outcomes. For continuous outcomes, we used the formula described in Table 7.7a in Section 7.7.3.8 of the Cochrane Handbook for Systematic Reviews of Interventions to combine means and standard deviations (Higgins 2011).

Manejo de los datos faltantes

We contacted investigators or study sponsors to verify key study characteristics and to obtain missing numerical outcome data when possible (e.g. when a study was identified as an abstract only). When this was not possible, and the missing data were thought to introduce serious bias, we explored the impact of including such studies in the overall assessment of results by performing a sensitivity analysis.

Evaluación de la heterogeneidad

We used the I² statistic to measure heterogeneity among the trials in each analysis. If we identified substantial heterogeneity (I² greater than 50%), we reported this and explored possible causes by performing prespecified subgroup analysis.

Evaluación de los sesgos de notificación

If we had been able to pool more than 10 trials, we planned to create and examine a funnel plot to explore possible small‐study and publication biases.

Síntesis de los datos

We used a random‐effects model and performed a sensitivity analysis using a fixed‐effect model. We applied a fixed‐effect model if the I² statistic showed homogeneous results, and a random‐effects model for data synthesis when there was significant heterogeneity (I² greater than 50%) that could not be explained by subgroup analyses.

We combined dichotomous outcome variables using a Mantel‐Haenszel OR with 95% CIs. For continuous outcomes, we analysed data as MDs with 95% CIs. We calculated the number needed to treat for an additional beneficial outcome (NNTB) from the pooled OR and assumed control risk using the formula described in Section 12.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

'Summary of findings' tables

We created 'Summary of findings' tables using the following outcomes.

  • Exacerbations requiring a short course of an oral steroid or antibiotic, or both.

  • Quality of life.

  • Non‐fatal SAEs.

  • Hospital admissions due to exacerbations.

  • Improvement in symptoms.

  • Change in lung function (trough FEV1).

  • Adverse events not including SAEs.

We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it related to the studies that contributed data to the meta‐analyses for prespecified outcomes. We applied methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software. We justified all decisions to downgrade or upgrade the certainty of studies by using footnotes, and we made comments to aid readers' understanding of the review when necessary.

Análisis de subgrupos e investigación de la heterogeneidad

We planned to carry out the following subgroup analyses.

  • Dose of LABAs (e.g. formoterol 6 µg, formoterol 12 µg, formoterol 18 µg).

  • Different LABAs (e.g. formoterol, salmeterol, indacaterol).

  • Concurrent use of ICS (dichotomised as yes/no).

We planned to use the following outcomes in subgroup analyses.

  • Exacerbations requiring a short course of an oral steroid or antibiotic, or both.

  • Quality of life.

  • Non‐fatal SAEs.

  • Improvement in symptoms.

We used the formal test for subgroup interactions provided in Review Manager 5 (Review Manager 2014).

Análisis de sensibilidad

We planned to carry out the following sensitivity analyses.

  • Repeating the meta‐analysis after exclusion of trials with high risk of bias or unclear methodological data.

  • Performing the meta‐analysis by using both a random‐effects model and a fixed‐effect model.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies tables for detailed description.

Results of the search

We conducted the initial search of the Cochrane Airways Group Specialised Register of trials (CAGR) on 11 March 2015 and the search of other sources (www.clinicaltrials.gov; WHO ICTRP; Almirall) on 13 March 2015, 29 March 2015 and 1 April 2015, respectively with no restriction on language. Updated search was performed in August 2017 for CAGR and September 2017 for other sources. Since the aclidinium trials had been taken over by AstraZeneca, we searched their website (AstraZeneca) in 2017. A prepublication literature search update was done on 12 October 2018.

We identified 384 (132 plus 178 plus 74) records from the CAGR, 104 (89 plus 15) from WHO ICTRP, 43 (21 plus 22) from www.clinicaltrials.gov, 25 (two plus 23) from Almirall and AstraZeneca clinical trial registry, and one from a reference list. After removal of duplicates, we screened the titles and abstracts of 387 records for eligibility and excluded 323 reports as obviously irrelevant based on title and abstract. We thoroughly studied the remaining 64 references for further assessment, retrieving full‐text articles where applicable. From our search, we excluded 23 references for 13 studies with complete agreement between the review authors. Details of studies that failed to meet the inclusion criteria were recorded in the Characteristics of excluded studies table. We identified seven studies reported in 38 references that were eligible for inclusion. There was one ongoing study with estimated completion date in 2018 (AVANT). We identified one study with two references that had completed recently with no published results for further classification (AMPLIFY). For details of the search results, see Figure 1.

Figure 1
Study flow diagram.

Study flow diagram.

Included studies

See Table 1 for an overview of the included studies.

Open in table viewer
Table 1. Overview of included studies

Study

Duration of study

Number randomised

Intervention

Comparison

ACLIFORM COPD

24 weeks

1729

Inhaled FDC aclidinium/formoterol 400/6 μg twice daily

Inhaled FDC aclidinium/formoterol 400/12 μg twice daily

Inhaled aclidinium 400 μg twice daily

Inhaled formoterol 12 μg twice daily

Inhaled placebo twice daily

ACTIVATE

8 weeks

267

Inhaled FDC aclidinium/formoterol 400/12 μg twice daily

Inhaled placebo twice daily

AUGMENT COPD

24 weeks

1692

Inhaled FDC aclidinium/formoterol 400/6 μg twice daily

Inhaled FDC aclidinium/formoterol 400/12 μg twice daily

Inhaled aclidinium 400 μg twice daily

Inhaled formoterol 12 μg twice daily

Inhaled placebo twice daily

D'Urzo 2017a

(extension study of AUGMENT COPD)

28 weeks

921

Inhaled FDC aclidinium/formoterol 400/6 μg twice daily

Inhaled FDC aclidinium/formoterol 400/12 μg twice daily

Inhaled aclidinium 400 μg twice daily

Inhaled formoterol 12 μg twice daily

Inhaled placebo twice daily

Donohue 2016

52 weeks

590

Inhaled FDC aclidinium/formoterol 400/12 μg twice daily

Inhaled formoterol 12 μg twice daily

NCT00706914

4 weeks

156

Inhaled FDC aclidinium/formoterol 200/12 μg once daily in the morning and placebo once daily in the evening

Inhaled FDC aclidinium/formoterol 200/12 μg once daily in the morning and formoterol 12 μg once daily in the evening

Inhaled formoterol 12 μg twice daily

Sliwinski 2010

4 weeks

566

Inhaled FDC aclidinium/formoterol 400/6 μg once daily

Inhaled FDC aclidinium/formoterol 400/12 μg once daily

Inhaled FDC aclidinium/formoterol 400/18 μg once daily

Inhaled aclidinium 200 μg once daily

Inhaled formoterol 12 μg once daily

Inhaled placebo once daily

FDC: fixed‐dose combination.

Study design, duration and setting

All the included trials were double‐blind, randomised, parallel‐group studies, assessing combined aclidinium bromide/formoterol as FDC in one inhaler. Four trials were active comparator (aclidinium/formoterol) and placebo controlled (ACLIFORM COPD; AUGMENT COPD; D'Urzo 2017a; Sliwinski 2010), two trials compared FDC with formoterol (Donohue 2016; NCT00706914), and one trial assessed FDC versus placebo (ACTIVATE). Four trials were phase three studies (ACLIFORM COPD; AUGMENT COPD; Donohue 2016; D'Urzo 2017a), two were phase two studies (NCT00706914; Sliwinski 2010), and one was a phase four study (ACTIVATE). D'Urzo 2017a was the 28‐week extension study of AUGMENT COPD, in which the participants who agreed for this extension study were kept on the same treatment and placebo arms as in the primary study.

The total duration of studies ranged from four to 52 weeks, with a mean of 20.6 weeks. Four of the included trials were of long duration with two studies of 24 weeks (ACLIFORM COPD; AUGMENT COPD), one study of 28 weeks (D'Urzo 2017a), and one study of 52 weeks (Donohue 2016). The remaining studies were of four weeks' (NCT00706914; Sliwinski 2010) and eight weeks' duration (ACTIVATE).

Most of the studies were based in the US (AUGMENT COPD; D'Urzo 2017a; Donohue 2016; NCT00706914), Canada (ACTIVATE; AUGMENT COPD; D'Urzo 2017a), Europe (ACLIFORM COPD; ACTIVATE; Sliwinski 2010), and Australia and New Zealand (AUGMENT COPD; Sliwinski 2010). Other study locations were South Africa (ACLIFORM COPD), and Asian countries of South Korea (ACLIFORM COPD), and India, Malaysia and Taiwan (Sliwinski 2010).

Participants

The seven eligible studies randomised 5921 participants. ACLIFORM COPD was the largest trial with 1729 participants, while NCT00706914 had the least number of participants with only 156. The number of participants of other studies ranged from 267 to 1692.

The participants men and women aged 40 years or older, who were current or former cigarette smokers with a smoking history of 10 or more pack‐years and diagnosed with stable moderate‐to‐severe airway obstruction according to GOLD criteria (postbronchodilator FEV1/FVC ratio less than 70% and FEV1 30% or greater but less than 80% of predicted normal value). The mean age of participants ranged from 60.7 to 64.7 years, with more men (3555) than women (2366). More than 90% of the participants were white in three studies (ACLIFORM COPD; AUGMENT COPD; D'Urzo 2017a); the other studies did not specify the race of the participants. The percentage of current smokers ranged from 43.9% to 63.4%, with mean smoking of 46.4 pack‐years to 61.3 pack‐years. Participants had moderate‐to‐severe COPD according to GOLD criteria though Sliwinski 2010 did not mention the specific criteria used for severity assessment. The participants' mean postbronchodilator FEV1 was between 50.5% and 61% of predicted normal with their baseline mean FEV1 ranging from 1.23 L to 1.43 L.

Interventions

All included trials assessed the efficacy and safety of combined aclidinium bromide/formoterol as FDC in one inhaler and we found no trials assessing the combination of aclidinium with other LABAs or in separate inhalers. The participants underwent a two‐ to three‐week run‐in period for disease stability and washout of disallowed medications in three trials (ACLIFORM COPD; AUGMENT COPD; Donohue 2016), while the duration of run‐in and screening period was 11 to 17 days in ACTIVATE. Six trials had a treatment arm of FDC of aclidinium 400 μg plus formoterol 12 μg (FDC 400/12 μg) (ACLIFORM COPD; ACTIVATE; AUGMENT COPD; D'Urzo 2017a; Donohue 2016; NCT00706914), and three studies assessed aclidinium/formoterol FDC 400/6 μg (ACLIFORM COPD; AUGMENT COPD; D'Urzo 2017a). Dose of aclidinium in FDC investigated in the initial phases of clinical development was 200 μg, which was later proved to be suboptimal (Sliwinski 2010).

Three main studies assessed two doses of FDC (400/6 μg, 400/12 μg) (ACLIFORM COPD; AUGMENT COPD; D'Urzo 2017a), and one study assessed three doses of FDC (200/6 μg, 200/12 μg, 200/18 μg) (Sliwinski 2010), in comparison to aclidinium monotherapy, formoterol monotherapy and placebo. D'Urzo 2017a was the extension of AUGMENT COPD in which consented participants who completed the primary study remained on the same intervention arm in a double‐blind method for another 28 weeks. Two studies compared FDC 400/12 μg to formoterol (Donohue 2016; NCT00706914), and one study compared FDC 400/12 μg versus placebo (ACTIVATE).

Three trials delivered FDC, aclidinium monotherapy, formoterol monotherapy and placebo twice daily via Genuair inhaler (ACLIFORM COPD; AUGMENT COPD; D'Urzo 2017a), and one trial delivered them once daily (Sliwinski 2010). One trial administered FDC 400/12 μg and formoterol 12 μg twice daily (Donohue 2016). One trial studied twice‐daily FDC 400/12 μg versus placebo (ACTIVATE). One trial allocated participants into three arms, both intervention arms received FDC 200/12 μg once daily in the morning with placebo in the evening in one arm and formoterol in the evening in the other arm; along with the comparator arm of formoterol 12 μg twice daily, all delivered via Genuair inhaler (NCT00706914).

Concomitant medications

Five studies with full‐text publications stated that participants were permitted to continue ICSs, oral or parenteral corticosteroids at doses equivalent to prednisolone of 10 mg/day or less or 20 mg every other day, oxygen therapy for less than 15 hours per day, provided treatment was stable for at least four weeks prescreening as well as the use of albuterol/salbutamol as rescue medication (ACLIFORM COPD; ACTIVATE; AUGMENT COPD; D'Urzo 2017a; Donohue 2016). Four trials permitted oral sustained‐release methylxanthines (ACLIFORM COPD; AUGMENT COPD; D'Urzo 2017a; Donohue 2016), though one trial prohibited it (ACTIVATE). Four trials did not permit any bronchodilator treatment other than the investigative and rescue medications (ACTIVATE; AUGMENT COPD; D'Urzo 2017a; Donohue 2016). The remaining two studies were in abstract form and there was no detailed description with respect to concomitant medications (NCT00706914; Sliwinski 2010).

Outcomes

The primary outcomes of the included studies and our review's primary outcomes were not the same since most of the individual trials assessed lung function as the primary outcome. Change from baseline in trough FEV1 (ACLIFORM COPD; AUGMENT COPD; Donohue 2016; Sliwinski 2010) and one‐hour postmorning dose FEV1 (ACLIFORM COPD; AUGMENT COPD) were the primary outcomes in individual trials which were analysed as secondary outcomes in our review. Other lung function parameters such as change from baseline in trough functional residual capacity (ACTIVATE), normalised FEV1 area under the curve, peak FEV1 (Sliwinski 2010) were also studied as primary outcomes whereas lung function tests with no further specification were the secondary outcomes for NCT00706914.

Quality of life measured by the SGRQ total score, one of the primary outcomes of our review, was studied in the two pivotal trials as secondary outcome (ACLIFORM COPD; AUGMENT COPD), and we analysed as both change from the baseline and percentage of participants with at least four unit decrease (minimal clinically important difference).

The safety data on adverse events not including SAEs, non‐fatal SAEs and mortality of all cause were studied as primary (Donohue 2016; D'Urzo 2017a) and secondary outcomes (ACLIFORM COPD; AUGMENT COPD; Sliwinski 2010), and well reported in the full‐text publications as well as in the European Public Assessment Report (EPAR). Though it is unlikely that a 24‐week study is long enough to demonstrate a clinically meaningful effect on exacerbations, necessary information regarding the number of participants with hospital admissions due to exacerbations and exacerbations who required a short course of oral steroids or antibiotics, or both were provided by the study sponsors. Improvement in symptoms measured in TDI score was studied as secondary outcome in ACLIFORM COPD and AUGMENT COPD, reported in the respective publications. Data in the format required for the meta‐analysis of some of the outcomes, especially SGRQ and TDI score, were kindly provided on request.

Funding

All studies were sponsored by Almirall (SA, Barcelona, Spain) and Forest Laboratories, Inc (New York, USA) or Menarini Group through its affiliate Berlin‐Chemie and AstraZeneca.

Excluded studies

Thirteen trials did not meet our eligibility criteria, seven were of cross‐over study design, four studied aclidinium bromide/formoterol fumarate combination with no comparator arm according to our review, one assessed the preference between Genuair and HandiHaler inhalers, and one was withdrawn prior to enrolment (ASTUTE) (see Characteristics of excluded studies table for details).

Risk of bias in included studies

Assessments of risk of bias in included studies are presented in detail in the Characteristics of included studies table and Figure 2.

Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

The published article on ACLIFORM COPD mentioned allocation using a centralised interactive voice response system with stratification by smoking status (smoker or ex‐smoker) in detail. The study concealed treatment identity with identical packaging/appearance and no odour or colour. AUGMENT COPD and its extension study D'Urzo 2017a generated randomisation codes by statistical programming and implemented by an interactive web response system. Donohue 2016 used a similar interactive web response system provided by Premier Research Group Limited (East Hartford, CT, USA) to assign patient identification numbers. Thus, the risk of bias for selection and allocation was low for these studies. However, the remaining trials were at unclear risk as they did not mention random sequence generation and allocation details (ACTIVATE; NCT00706914; Sliwinski 2010).

Blinding

All the included trials were double blind where investigators, participants and carers were unaware of the intervention received. Therefore, we judged these studies at low risk of bias. Investigators administered the study drugs in a double‐blind pattern where neither the attending physician nor the participant knew which intervention arm a particular participant was in. Furthermore, the study medications were in identical packaging or of appearance and delivered by a similar inhaler device. All inhalers were identical from an external perspective where the only difference between them was that placebo did not contain active ingredient. The active ingredients had no perceptible taste, appearance, odour or colour that could unmask the blinding. Independent adjudication committee members who were not participating in the study and were blinded to treatment evaluated outcomes. For safety outcomes, blinded independent expert cardiologists not participating in the study performed the assessment of major adverse cardiac events (D'Urzo 2017a; Donohue 2016).

Incomplete outcome data

All included studies reported with reasons the total number of withdrawals for each study arm in full‐text articles (ACLIFORM COPD; ACTIVATE; AUGMENT COPD; D'Urzo 2017a; Donohue 2016) or the study results from the clinicaltrials.gov (NCT00706914; Sliwinski 2010). The withdrawal rates were relatively low with similar reasons across the study arms in four trials (ACLIFORM COPD; ACTIVATE; NCT00706914; Sliwinski 2010), thus the risk of attrition bias for these studies was low. We assessed the attrition bias for the remaining three studies as unclear because the dropout rates were high even though they were relatively similar among the study arms (AUGMENT COPD; D'Urzo 2017a; Donohue 2016). All studies performed efficacy by intention to treat and safety analysis in the safety population, which was defined as all randomised participants who had received at least one dose of study medication.

Selective reporting

Both full‐text publications and clinical study synopses described the results of all prespecified outcomes for all included studies, without obvious reporting bias. Moreover, trial result summaries for those started in late 2015 and beyond were available on the AztraZeneca website regardless of the positive or negative effects of the study medication which made reporting bias very unlikely. However, ACLIFORM COPD did not report data on the percentage of participants with clinically significant improvement in SGRQ total score of at least four units for FDC compared to formoterol in any of the published texts despite reporting the absolute change of SGRQ score for these arms, thus this study was at unclear risk of reporting bias.

Other potential sources of bias

Almirall funded the initial six trials (ACLIFORM COPD; AUGMENT COPD; D'Urzo 2017a; Donohue 2016; NCT00706914; Sliwinski 2010) and AstraZeneca sponsored the latest trial (ACTIVATE) following the agreement between Almirall and AztraZeneca on the transition of the Almirall respiratory studies. Study authors disclosed any possible conflicts of interest, both financial and non‐financial, in the published articles, thus we detected no other possible sources of bias.

Effects of interventions

See: Summary of findings for the main comparison Fixed‐dose combination aclidinium/formoterol compared to aclidinium alone for chronic obstructive pulmonary disease (COPD); Summary of findings 2 Fixed‐dose combination aclidinium/formoterol compared to formoterol for chronic obstructive pulmonary disease (COPD); Summary of findings 3 Fixed‐dose combination aclidinium/formoterol compared to placebo for chronic obstructive pulmonary disease (COPD)

We only identified trials on combined aclidinium bromide and formoterol in FDC and included data from all studies except D'Urzo 2017a for quantitative synthesis (meta‐analysis). We compared FDC of aclidinium bromide/formoterol versus aclidinium, formoterol and placebo. None of the seven studies were designed to enrol people with exacerbation‐prone COPD. None of the included studies required participants to have at least two prior year exacerbations or at least one prior year hospitalisation. Therefore, there were no currently published studies of aclidinium/formoterol specifically designed or powered to look for benefits on COPD exacerbation endpoints for dual therapy versus monotherapy.

1. Fixed‐dose combination aclidinium/formoterol versus aclidinium alone

Primary outcomes
Exacerbations requiring a short course of an oral steroid or antibiotic, or both

Analysis of 2156 participants from two trials found no evidence of a difference between FDC aclidinium/formoterol and aclidinium alone for the number of participants experiencing at least one exacerbation requiring a short course of oral steroids or antibiotics, or both over 24 weeks (OR 0.95, 95% CI 0.71 to 1.27; moderate‐certainty evidence; Analysis 1.1) (ACLIFORM COPD; AUGMENT COPD). Published articles did not report this outcome, however, the sponsors provided the data necessary for this analysis. Subgroup analysis for the FDC doses of formoterol 12 μg (OR 0.91, 95% CI 0.60 to 1.39; 2 trials, 1080 participants) and 6 μg (OR 0.99, 95% CI 0.65 to 1.49; 2 trials, 1076 participants) demonstrated a similar result with no evidence of a difference between the subgroups (test for subgroup differences: P = 0.80).

Quality of life

Two trials studied quality of life as change from baseline in SGRQ total score as well as the number of participants who attained a minimal clinically significant reduction of at least four units (ACLIFORM COPD; AUGMENT COPD). From the meta‐analysis of 2002 participants, there was no evidence of a difference in change from baseline of mean SGRQ total score with FDC aclidinium/formoterol compared to aclidinium alone (MD –0.92, 95% CI –2.15 to 0.30; Analysis 1.2). There was no evidence of a difference over aclidinium monotherapy for FDC doses using formoterol 12 μg (MD –0.77. 95% CI –2.51 to 0.96; 2 trials, 1004 participants) and 6 μg (MD –1.08, 95% CI –2.81 to 0.65; 2 trials, 998 participants) (test for subgroup differences: P = 0.81).

This translated into no evidence of a difference in the number of participants who achieved a minimal clinically important improvement of SGRQ total score reduction of at least four units over 24 weeks between FDC aclidinium/formoterol and aclidinium alone (OR 1.17, 95% CI 0.97 to 1.41; 2 trials, 2002 participants; Analysis 1.3). In absolute terms, 579/1000 participants (95% CI 533/1000 to 624/1000) treated with FDC aclidinium/formoterol reported a clinically important improvement in quality of life while 541/1000 participants taking aclidinium alone experienced the same improvement (moderate‐certainty evidence; summary of findings Table for the main comparison). Neither of the FDC doses containing formoterol 12 μg (OR 1.12, 95% CI 0.86 to 1.45; 2 trials, 1004 participants) nor 6 μg (OR 1.22, 95% CI 0.93 to 1.59; 2 trials, 998 participants) demonstrated a significant improvement over aclidinium (test for subgroup differences: P = 0.65).

Non‐fatal serious adverse events

The pooled analysis of data from three studies revealed no evidence of a difference in non‐fatal SAEs between FDC aclidinium/formoterol and aclidinium alone groups (OR 1.19, 95% CI 0.79 to 1.80; 2473 participants; moderate‐certainty evidence; Analysis 1.4) (ACLIFORM COPD; AUGMENT COPD; Sliwinski 2010). In 1000 participants, 49 (95% CI 33 to 72) in the FDC aclidinium/formoterol group developed non‐fatal SAEs compared to 41 in the aclidinium alone group (summary of findings Table for the main comparison). Subgroup analysis showed no evidence of a difference between the FDC dose of formoterol 12 μg (OR 1.32, 95% CI 0.74 to 2.36; 3 trials, 1238 participants) and 6 μg (OR 1.07, 95% CI 0.60 to 1.92; 3 trials, 1235 participants) (test for subgroup differences: P = 0.62).

Secondary outcomes
Mortality

Three trials reported the total number of deaths. There were no deaths in either FDC aclidinium/formoterol and aclidinium alone arms in Sliwinski 2010 during the four‐week study period (ACLIFORM COPD; AUGMENT COPD; Sliwinski 2010). The total number of deaths due to all causes was not significantly different between FDC aclidinium/formoterol‐treated and aclidinium‐treated participants (Peto OR 0.66, 95% CI 0.14 to 3.16; 3 trials, 2473 participants; Analysis 1.5).

Hospital admissions due to exacerbations

Meta‐analysis of data from two studies demonstrated no evidence of a difference in the number of participants who required at least one hospital admission due to severe exacerbations between FDC aclidinium/formoterol and aclidinium alone (OR 0.62, 95% CI 0.29 to 1.29; 2156 participants; moderate‐certainty evidence; Analysis 1.6) (ACLIFORM COPD; AUGMENT COPD). Neither FDC with formoterol 12 µg (OR 0.58, 95% CI 0.19 to 1.74; 2 trials, 1080 participants) nor FDC with formoterol 6 µg (OR 0.65, 95% CI 0.24 to 1.75; 2 trials, 1076 participants) were associated with a significant reduction in hospitalisations compared to aclidinium monotherapy (test for subgroup differences: P = 0.88). Among 1000 participants, 11 (95% CI 5 to 23) in the FDC aclidinium/formoterol group and 18 in the aclidinium alone group experienced at least one severe COPD exacerbation necessitating hospital admission (summary of findings Table for the main comparison).

Improvement in symptoms

Two studies assessed symptomatic improvement in dyspnoea by TDI focal score as the change from baseline in mean value to the end of the study over 24 weeks as well as the number of participants with at least one unit increment which was of minimal clinically important difference (ACLIFORM COPD; AUGMENT COPD). Overall, FDC aclidinium/formoterol significantly increased TDI focal score from baseline with an MD of 0.37 units compared to aclidinium (95% CI 0.07 to 0.68; 2013 participants; Analysis 1.7; Figure 3). Similarly, FDC aclidinium/formoterol was associated with a statistically significant difference in the number of participants with at least one unit improvement in TDI focal score compared to aclidinium alone (OR 1.34, 95% CI 1.11 to 1.62; 2013 participants; Analysis 1.8). In absolute terms, 627/1000 (95% CI 582 to 671) participants receiving FDC aclidinium/formoterol reported a clinically significant symptomatic improvement compared to 557/1000 participants given aclidinium alone, indicating 70 more (25 more to 114 more) participants attained this improvement. Thus, for every 14 participants given FDC aclidinium/formoterol, one more person experienced a clinically important improvement of at least one unit increase in TDI focal score (95% CI 9 to 39, high‐certainty evidence; summary of findings Table for the main comparison).

Figure 3
Forest plot of comparison: 1 Fixed‐dose combination (FDC) aclidinium and formoterol versus aclidinium, Outcome: 1.7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score.

Forest plot of comparison: 1 Fixed‐dose combination (FDC) aclidinium and formoterol versus aclidinium, Outcome: 1.7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score.

Upon subgroup analyses, both FDC doses containing formoterol 12 µg (MD 0.42, 95% CI –0.01 to 0.85; 2 trials, 1012 participants) and formoterol 6 µg (MD 0.33, 95% CI –0.10 to 0.76; 2 trials, 1001 participants) showed no significant change from baseline TDI focal score (test for subgroup differences: P = 0.76; Analysis 1.7). Likewise, there was no evidence of a difference between FDC containing formoterol 12 µg (OR 1.28, 95% CI 0.98 to 1.67; 2 trials, 1012 participants) and formoterol 6 µg (OR 1.40, 95% CI 1.08 to 1.84; 2 trials, 1001 participants) in the proportion of participants with clinically important symptomatic improvement of at least one unit change in TDI focal score (test for subgroup differences: P = 0.62; Analysis 1.8).

Change in lung function

Three trials assessed trough FEV1 (ACLIFORM COPD; AUGMENT COPD; Sliwinski 2010), two of which also reported one‐hour postmorning dose FEV1 as the change from baseline in mean value at the end of the study (ACLIFORM COPD; AUGMENT COPD). From the meta‐analysis of these data, we observed that FDC aclidinium/formoterol compared to aclidinium alone significantly improved both trough FEV1 (MD 0.02, 95% CI 0.00 to 0.04; 3 trials, 2333 participants; high‐certainty evidence; Analysis 1.9; summary of findings Table for the main comparison) and postmorning dose FEV1 (MD 0.10, 95% CI 0.08 to 0.12; 2 trials, 2018 participants; Analysis 1.10). Subgroup analysis for trough FEV1 demonstrated a significant improvement compared to aclidinium alone with FDC dose containing formoterol 12 µg (MD 0.04, 95% CI 0.01 to 0.06; 3 trials, 1171 participants) and a non‐significant difference for FDC dose containing formoterol 6 µg (MD 0.01, 95% CI –0.02 to 0.04; 3 trials, 1162 participants). However, there was no evidence of a difference between the two doses of formoterol (test for subgroup differences: P = 0.16; Analysis 1.9). For postmorning dose FEV1, both FDC containing formoterol 12 µg (MD 0.12, 95% CI 0.09 to 0.15; 2 trials, 1013 participants) and formoterol 6 µg (MD 0.08, 95% CI 0.05 to 0.11; 2 trials, 1005 participants) produced a significant improvement compared with aclidinium alone (test for subgroup differences: P = 0.09; Analysis 1.10).

Adverse events not including SAEs

From the pooled analysis of data of three trials, there was no evidence of a difference between FDC aclidinium/formoterol and aclidinium alone for the number of participants experiencing adverse events, not including SAEs (OR 0.95, 95% CI 0.76 to 1.18; 2473 participants; Analysis 1.11) (ACLIFORM COPD; AUGMENT COPD; Sliwinski 2010). Both doses of formoterol 12 µg (OR 0.93, 95% CI 0.68 to 1.27; 3 trials, 1238 participants) and 6 µg (OR 0.97, 95% CI 0.71 to 1.31; 3 trials, 1235 participants) showed similar results (test for subgroup differences: P = 0.85, Figure 4). In absolute terms, 186/1000 participants (95% CI 155 to 221) in the FDC aclidinium/formoterol group had adverse events compared with 194/1000 in the aclidinium alone group (moderate‐certainty evidence; summary of findings Table for the main comparison).

Figure 4
Forest plot of comparison: 1 Fixed‐dose combination (FDC) aclidinium and formoterol versus aclidinium, Outcome: 1.11 Number of participants with adverse events (not including serious adverse events).

Forest plot of comparison: 1 Fixed‐dose combination (FDC) aclidinium and formoterol versus aclidinium, Outcome: 1.11 Number of participants with adverse events (not including serious adverse events).

2. Fixed‐dose combination aclidinium/formoterol versus formoterol alone

Primary outcomes
Exacerbations requiring a short course of an oral steroid or antibiotic, or both

Three trials reported exacerbations requiring a short course of an oral steroid or antibiotic, or both (ACLIFORM COPD; AUGMENT COPD; Donohue 2016). Overall analysis of data from these trials demonstrated a statistically significant reduction in the number of participants experiencing at least one exacerbation requiring a short course of an oral steroid or antibiotic, or both, with FDC aclidinium/formoterol compared to formoterol alone (OR 0.78, 95% CI 0.62 to 0.99; 3 trials, 2694 participants; high‐certainty evidence; Analysis 2.1). In absolute terms, 124/1000 participants (95% CI 101 to 152) receiving FDC aclidinium/formoterol had at least one exacerbation compared to 154/1000 participants receiving formoterol alone; thus FDC aclidinium/formoterol resulted in 30 fewer (2 to 53 fewer) participants with a moderate exacerbation than formoterol alone (summary of findings Table 2). Subgroup analysis showed that the difference between formoterol 12 µg (OR 0.75, 95% CI 0.56 to 1.00; 3 trials, 1622 participants) and formoterol 6 µg (OR 0.85, 95% CI 0.57 to 1.26; 2 trials, 1072 participants) was not statistically significant (test for subgroup differences: P = 0.64, Figure 5).

Figure 5
Forest plot of comparison: 2 Fixed‐dose combination (FDC) aclidinium and formoterol versus formoterol, Outcome: 2.1 Number of participants with exacerbations requiring steroids or antibiotics or both.

Forest plot of comparison: 2 Fixed‐dose combination (FDC) aclidinium and formoterol versus formoterol, Outcome: 2.1 Number of participants with exacerbations requiring steroids or antibiotics or both.

Quality of life

Two trials assessed quality of life reported as the change in mean SGRQ total score from baseline towards the end of the study (24 weeks) (ACLIFORM COPD; AUGMENT COPD); however, ACLIFORM COPD did not report the proportion of participants who attained a minimal clinically important difference of at least four units' reduction in the score. FDC aclidinium/formoterol revealed a statistically significant improvement in change from baseline in mean SGRQ total score with a mean difference of –1.88 compared to formoterol alone (95% CI –3.10 to –0.65; 2 trials, 2002 participants; Analysis 2.2); however, it found no significant improvement in the number of participants achieving at least four units reduction (OR 1.15, 95% CI 0.89 to 1.50; 1 trial, 1000 participants; Analysis 2.3). Further subgroup analysis indicated no significant improvement with formoterol 12 µg (MD –1.72, 95% CI –3.45 to 0.02; 2 trials, 1005 participants) and a significant reduction for FDC with formoterol 6 µg (MD –2.03, 95% CI –3.76 to –0.30; 2 trials, 997 participants); however, the difference was not significant between the two groups (test for subgroup differences: P = 0.80; Analysis 2.2). In a population of 1000, 559 (95% CI 495 to 623) participants taking FDC had at least a four‐unit reduction in SGRQ total score compared with 524 participants taking formoterol alone (low‐certainty evidence, summary of findings Table 2).

Non‐fatal serious adverse events

Five trials reported participants with non‐fatal SAEs for FDC aclidinium/formoterol and formoterol alone, the pooled analysis of which showed no evidence of a difference between them (OR 1.15, 95% CI 0.82 to 1.61; 5 trials, 3140 participants; Analysis 2.4) (ACLIFORM COPD; AUGMENT COPD; Donohue 2016; NCT00706914; Sliwinski 2010). In a population of 1000, 58 (95% CI 42 to 79) participants in the FDC aclidinium/formoterol group and 50 participants in the formoterol alone group had a non‐fatal SAE (moderate‐certainty evidence; summary of findings Table 2). The difference between FDCs containing formoterol 12 µg (OR 1.13, 95% CI 0.76 to 1.70; 5 trials, 1914 participants) and formoterol 6 µg (OR 1.20, 95% CI 0.65 to 2.20; 3 trials, 1226 participants) were not statistically significant (test for subgroup differences: P = 0.88).

Secondary outcomes
Mortality

Five trials stated the number of deaths in published articles (ACLIFORM COPD; AUGMENT COPD; Donohue 2016; NCT00706914; Sliwinski 2010); however, two of them reported no death during the study period (NCT00706914; Sliwinski 2010). There was no evidence of a difference between FDC aclidinium/formoterol and formoterol alone for the all‐cause mortality (Peto OR 1.46, 95% CI 0.44 to 4.87; 5 trials, 3140 participants; Analysis 2.5).

Hospital admissions due to exacerbations

Three trials assessed the number of participants with severe exacerbations requiring hospital admissions and the meta‐analysis found no difference between FDC aclidinium/formoterol and formoterol alone (OR 0.76, 95% CI 0.45 to 1.28; 2694 participants; Analysis 2.6) (ACLIFORM COPD; AUGMENT COPD; Donohue 2016). In a total of 1000 participants receiving FDC aclidinium/formoterol, 20 (95% CI 12 to 34) would require admission compared to 27 from the formoterol alone group (moderate‐certainty evidence; summary of findings Table 2). Subgroup analysis showed no difference between an FDC formoterol dose of 12 µg (OR 0.69, 95% CI 0.38 to 1.25; 3 trials, 1622 participants) and formoterol 6 µg (OR 1.06, 95% CI 0.34 to 3.28; 2 trials, 1072 participants) (test for subgroup differences: P = 0.51).

Improvement in symptoms

Two trials studied symptomatic improvement in terms of TDI focal score as change from baseline to the end of the study (24 weeks) as well as the percentage of participants who achieved a minimal clinically important difference of one unit improvement in the score (ACLIFORM COPD; AUGMENT COPD). Overall, FDC aclidinium/formoterol was associated with a significant improvement in TDI focal score change from baseline compared with formoterol alone (MD 0.42, 95% CI 0.11 to 0.72; 2 trials, 2010 participants; Analysis 2.7). Subgroup analysis of the FDC formoterol dose of 12 µg found significant improvement (MD 0.47, 95% CI 0.03 to 0.90; 2 trials, 1011 participants) while formoterol 6 µg showed no significance (MD 0.37, 95% CI –0.06 to 0.80; 2 trials, 999 participants); however, test for subgroup differences was not significant (P = 0.76).

Similarly, FDC aclidinium/formoterol was significantly associated with a higher number of participants achieving a clinically important improvement in TDI focal score (OR 1.30, 95% CI 1.07 to 1.56; 2 trials, 2010 participants; Analysis 2.8). In absolute terms, for every 1000 participants, 628 (95% CI 582 to 670; 17 more to 105 more) taking FDC aclidinium/formoterol and 565 taking formoterol alone attained a clinically significant symptomatic improvement (high‐certainty evidence, summary of findings Table 2). Thus, for every 16 (95% CI 10 to 60) participants treated with FDC aclidinium/formoterol, one additional participant would attain the clinically important improvement of TDI focal score. Subgroup analysis of the dosage revealed no evidence of a difference between the subgroups (P = 0.57) of formoterol 12 µg (OR 1.23, 95% CI 0.94 to 1.60; 2 trials, 1011 participants) and formoterol 6 µg (OR 1.37, 95% CI 1.05 to 1.79; 2 trials, 999 participants).

Change in lung function

Four trials reported change from baseline in trough FEV1 (ACLIFORM COPD; AUGMENT COPD; NCT00706914; Sliwinski 2010), and two trials reported one‐hour postmorning dose FEV1 (ACLIFORM COPD; AUGMENT COPD). There was a significant improvement in trough FEV1 change from baseline with FDC aclidinium/formoterol compared to formoterol alone (MD 0.04, 95% CI 0.03 to 0.06; 4 trials, 2411 participants; high‐certainty evidence; Analysis 2.9; summary of findings Table 2). Both FDC formoterol dose of 12 µg (MD 0.05, 95% CI 0.03 to 0.08; 4 trials, 1254 participants) and formoterol 6 µg (MD 0.04, 95% CI 0.01 to 0.07; 3 trials, 1157 participants) had a statistically significant result with no difference between the two doses (test for subgroup differences: P = 0.52).

FDC aclidinium/formoterol also resulted in a significant improvement of one‐hour postmorning dose FEV1 compared with formoterol alone (MD 0.09, 95% CI 0.07 to 0.11; 2 trials, 2021 participants; Analysis 2.10). There was similar improvement for FDC dose of formoterol 12 µg (MD 0.11, 95% CI 0.08 to 0.14; 2 trials, 1015 participants) and formoterol 6 µg (MD 0.07, 95% CI 0.04 to 0.10; 2 trials, 1006 participants) with no evidence of a difference between the two doses (test for subgroup differences: P = 0.09).

Adverse events not including SAEs

Analysis of data from five trials found significantly fewer adverse events (not including SAEs) with FDC aclidinium/formoterol compared to formoterol (OR 0.78, 95% CI 0.65 to 0.93; 5 trials, 3140 participants; Analysis 2.11) (ACLIFORM COPD; AUGMENT COPD; Donohue 2016; NCT00706914; Sliwinski 2010). Upon subgroup analysis, there was no evidence of a difference between FDC dose of formoterol 12 µg (OR 0.79, 95% CI 0.63 to 0.99; 5 trials, 1914 participants) and formoterol 6 µg (OR 0.76, 95% CI 0.56 to 1.02; 3 trials, 1226 participants) with no evidence of a difference between the two doses (test for subgroup differences: P = 0.81). In a group of 1000 participants, 46 (95% CI 14 to 76 lower) fewer participants experienced adverse events if they received FDC aclidinium/formoterol compared to participants receiving formoterol alone (high‐certainty evidence; summary of findings Table 2). Thus, to achieve an additional person with no adverse events, 22 (95% CI 13 to 71) participants need to be treated with FDC aclidinium/formoterol.

3. Fixed‐dose combination aclidinium/formoterol versus placebo

Primary outcomes
Exacerbations requiring a short course of an oral steroid or antibiotic, or both

According to the analysis of data from two trials, FDC aclidinium/formoterol was not associated with significant reduction in the number of participants with exacerbations which required a short course of an oral steroid or antibiotic, or both, compared to placebo over the period of 24 weeks (moderate‐certainty evidence, OR 0.82, 95% CI 0.60 to 1.12; 2 trials, 1960 participants; Analysis 3.1) (ACLIFORM COPD; AUGMENT COPD). Both FDCs containing formoterol 12 µg (OR 0.82, 95% CI 0.52 to 1.28; 2 trials; 983 participants) and formoterol 6 µg showed no significance over placebo (OR 0.82, 95% CI 0.53 to 1.27; 2 trials, 977 participants), with no difference among the doses (test for subgroup differences: P = 0.99). In absolute terms, among 1000 participants, FDC caused 20 fewer (47 lower to 14 higher) participants with moderate exacerbation requiring steroids or antibiotics, or both, than placebo (summary of findings Table 3).

Quality of life

FDC aclidinium/formoterol produced a significant improvement in quality of life in terms of change from baseline in SGRQ total score (MD –2.91, 95% CI –4.33 to –1.50; 2 trials, 1823 participants; Analysis 3.2) as well as the number of participants with clinically important improvement of at least four units (OR 1.72, 95% CI 1.39 to 2.13; 2 trials, 1823 participants; Analysis 3.3) compared to placebo in two trials over 24 weeks (ACLIFORM COPD; AUGMENT COPD). Both FDCs containing formoterol 12 µg (MD –2.86, 95% CI –4.87 to –0.85; 2 trials, 915 participants) and formoterol 6 µg (MD –2.97, 95% CI –4.97 to –0.96; 2 trials, 908 participants) showed significant improvement in SGRQ total score over placebo, with no difference among the doses (test for subgroup differences: P = 0.94, Figure 6).

Figure 6
Forest plot of comparison: 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome: 3.2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score.

Forest plot of comparison: 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome: 3.2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score.

Both FDCs with formoterol 12 µg (OR 1.69, 95% CI 1.26 to 2.28; 2 trials, 915 participants) and formoterol 6 µg (OR 1.75, 95% CI 1.29 to 2.36; 2 trials, 908 participants) revealed a significant number of participants with SGRQ total score of at least four units' improvement (test for subgroup differences: P = 0.89). Among a population of 1000 participants, 568 taking FDC had a clinically important improvement in SGRQ total score of more than four units whereas only 433 of those given placebo resulted in similar response (difference 135, 95% CI 82 to 186 more). Thus, for every seven (95% CI five to 12) participants treated with FDC aclidinium/formoterol, one extra person would achieve a clinically important improvement in quality of life compared to placebo (high‐certainty evidence; summary of findings Table 3).

Non‐fatal serious adverse events

Four trials reported the number of participants with non‐fatal SAEs (ACLIFORM COPD; ACTIVATE; AUGMENT COPD; Sliwinski 2010). There was no evidence of a difference between FDC aclidinium/formoterol and placebo (OR 1.12, 95% CI 0.72 to 1.74; 4 trials, 2527 participants; moderate‐certainty evidence; Analysis 3.4). There was no difference between FDCs with formoterol 12 µg (OR 1.15, 95% CI 0.63 to 2.10; 4 trials, 1399 participants) and formoterol 6 µg (OR 1.09, 95% CI 0.56 to 2.09; 3 trials, 1128 participants), with no evidence of a difference between the subgroups (P = 0.90). In a group of 1000 participants, 42 (95% CI 27 to 64) receiving FDC aclidinium/formoterol and 38 receiving placebo experienced a non‐fatal SAE (summary of findings Table 3).

Secondary outcomes
Mortality

Three studies found no difference in the number of deaths between FDC aclidinium/formoterol and placebo (Peto OR 3.79, 95% CI 0.37 to 39.13; 3 trials, 2260 participants; Analysis 3.5) (ACLIFORM COPD; AUGMENT COPD; Sliwinski 2010). There were no reported deaths in Sliwinski 2010, which was a short duration study of four weeks.

Hospital admissions due to exacerbations

Two studies reported hospital admissions due to exacerbations (ACLIFORM COPD; AUGMENT COPD). There was no evidence of a difference in the number of participants with severe exacerbations who required hospital admissions between FDC aclidinium/formoterol and placebo (OR 0.55, 95% CI 0.25 to 1.18; 1960 participants; Analysis 3.6). Both FDCs with formoterol 12 µg (OR 0.49, 95% CI 0.15 to 1.60; 2 trials, 983 participants) and formoterol 6 µg (OR 0.59, 95% CI 0.21 to 1.65; 2 trials, 977 participants) revealed similar results, with no evidence of a difference between the subgroups (P = 0.83). In absolute terms, for a group of 1000 participants, 12 (95% CI 5 to 25) from the FDC aclidinium/formoterol group required hospitalisation due to exacerbations compared with 21 from the placebo group (moderate‐certainty evidence; summary of findings Table 3).

Improvement in symptoms

Two studies reported improvement in symptoms (ACLIFORM COPD; AUGMENT COPD). Compared to placebo, FDC aclidinium/formoterol showed significant improvement in terms of TDI focal score change from baseline over 24 weeks (MD 1.32, 95% CI 0.96 to 1.69; 1832 participants; Analysis 3.7). Both doses of FDC formoterol 12 µg (MD 1.37, 95% CI 0.85 to 1.88; 2 trials; 922 participants) and formoterol 6 µg (MD 1.28, 95% CI 0.77 to 1.80; 2 trials, 910 participants) showed significance over placebo with no difference between the two subgroups (P = 0.82).

Likewise, FDC aclidinium/formoterol was associated with a significantly higher number of participants with a minimal clinically significant improvement of TDI focal score one unit or more when compared with placebo (OR 2.51, 95% CI 2.02 to 3.11; 2 trials, 1832 participants; Analysis 3.8). This significant improvement was observed with FDCs containing formoterol 12 µg (OR 2.37, 95% CI 1.75 to 3.22; 2 trials, 922 participants) and formoterol 6 µg (OR 2.65, 95% CI 1.96 to 3.60; 2 trials, 910 participants). There was no difference between the subgroups (P = 0.61). In a group of 1000 participants, 620 (95% CI 568 to 669) taking FDC aclidinium/formoterol had at least one unit increment in TDI focal score compared with 394 for placebo group over 24 weeks' duration (high‐certainty evidence; summary of findings Table 3). One additional participant would achieve a minimal clinically significant increment of at least one unit in TDI focal score for every four (95% CI four to six) participants treated with FDC aclidinium/formoterol compared to placebo.

Change in lung function

Three trials studied change from baseline in trough FEV1 (ACLIFORM COPD; AUGMENT COPD; Sliwinski 2010), while two studies reported change from baseline in one‐hour post morning dose FEV1 (ACLIFORM COPD; AUGMENT COPD). FDC aclidinium/formoterol significantly improved trough FEV1 change from baseline compared with placebo (MD 0.12, 95% CI 0.10 to 0.14; 3 trials, 2137 participants; high‐certainty evidence; Analysis 3.9; summary of findings Table 3). There was no difference between FDCs with formoterol 12 µg (MD 0.13, 95% CI 0.10 to 0.16; 3 trials, 1073 participants) and formoterol 6 µg (MD 0.11, 95% CI 0.07 to 0.14; 3 trials, 1064 participants; test for subgroup differences: P = 0.25).

FDC aclidinium/formoterol also demonstrated a significant improvement in one‐hour postmorning dose FEV1 change from baseline compared to placebo (MD 0.27, 95% CI 0.25 to 0.30; 2 trials, 1842 participants; Analysis 3.10) with no difference between FDCs with formoterol 12 µg (MD 0.29 , 95% CI 0.25 to 0.33; 2 trials, 925 participants) and formoterol 6 µg (MD 0.25, 95% CI 0.22 to 0.29; 2 trials, 917 participants; test for subgroup differences: P = 0.17).

Adverse events not including SAEs

Four trials reported the number of participants experiencing adverse events not including SAEs (ACLIFORM COPD; ACTIVATE; AUGMENT COPD; Sliwinski 2010). There was no difference between FDC aclidinium/formoterol and placebo (OR 0.97, 95% CI 0.76 to 1.22; 2527 participants, moderate‐certainty evidence; Analysis 3.11). Both FDCs with formoterol 12 µg (OR 0.89, 95% CI 0.65 to 1.22; 4 trials, 1399 participants) and formoterol 6 µg (OR 1.07, 95% CI 0.75 to 1.53; 3 trials, 1128 participants) resulted in the similar response compared to placebo with no difference between the subgroups (P = 0.44). Out of 1000 participants, 171 (95% CI 139 to 206) in the FDC aclidinium/formoterol group would experience at least one adverse event compared with 175 for placebo group over a period of four to 24 weeks (summary of findings Table 3).

Discusión

disponible en

Resumen de los resultados principales

Solo se pudieron identificar los ensayos que evaluaron un tratamiento combinado de aclidinio/formoterol en un mismo inhalador, como CDF con una dosis de formoterol, o de 12 µg o de 6 µg. En comparación con aclidinio solo, la CDF de aclidinio/formoterol mejoró los síntomas de manera significativa, ya que la puntuación focal del TDI aumentó 0,37 unidades (de 0,07 a 0,68) aunque esta mejoría media no alcanzó el umbral aceptado de una unidad para una diferencia de importancia clínica. En comparación, hubo una cantidad significativamente mayor de pacientes que respondieron según el TDI con la CDF de aclidinio/formoterol que con aclidinio solo, con un NNTB de 14. La CDF de aclidinio/formoterol también mejoró la función pulmonar, tanto el valor mínimo del VEM1 como el VEM1 una hora después de la dosis de la mañana, aunque no hubo diferencias en cuanto a las exacerbaciones que requirieron esteroides, ni antibióticos, ni ninguno de ellos; calidad de vida; ingresos hospitalarios debidos a las exacerbaciones graves; mortalidad por todas las causas; EAG no mortales y otros eventos adversos en comparación con aclidinio.

En comparación con el formoterol solo, la CDF de aclidinio/formoterol demostró una mejoría importante en los síntomas; función pulmonar; calidad de vida; reducción de las exacerbaciones que requirieron un ciclo corto de esteroides o de antibióticos, o ambos y de los eventos adversos (no se incluyen los EAG). La CDF de aclidinio/formoterol se asoció con un aumento medio en la puntuación focal del TDI de 0,42 unidades (de 0,11 a 0,72 mayor) así como una mayor cantidad de pacientes que respondieron según el TDI que con formoterol (NNTB 16). El tratamiento combinado también disminuyó la puntuación total del SGRQ en 1,88 unidades (de 3,10 a 0,65 menor) en comparación con el formoterol, aunque esta mejoría media no logró una importancia clínica de cuatro unidades. Sin embargo, no hubo diferencias en los ingresos hospitalarios, ni en la mortalidad por todas las causas, ni en los EAG no mortales.

En comparación con el placebo, el tratamiento combinado mejoró significativamente la calidad de vida, los síntomas y la función pulmonar. La CDF de aclidinio/formoterol exhibió una reducción de importancia clínica de 2,91 unidades (de 4,33 a 1,50 menor) en la puntuación total del SGRQ con un NNTB de siete. Los participantes tratados con CDF de aclidinio/formoterol presentaron mayores mejorías de importancia clínica en la disnea, con una puntuación total de cambio respecto del valor inicial según el TDI de 1,32 unidades (IC del 95%: 0,96 a 1,69 unidades) en comparación con placebo. Para lograr un paciente adicional con al menos un aumento de una unidad en la puntuación focal según el TDI, hay que tratar a cuatro participantes. No hubo diferencias entre el tratamiento combinado y el placebo en cuanto a las exacerbaciones moderadas que requieren esteroides o antibióticos, o ambos; ingresos hospitalarios debidos a las exacerbaciones graves; mortalidad por todas las causas; eventos adversos y EAG no mortales.

Compleción y aplicabilidad general de las pruebas

Las últimas guías de la EPOC recomiendan administrar ABAP y AMAP combinados como una opción para los pacientes con EPOC de grupos B y C con síntomas persistentes o exacerbaciones adicionales y como tratamiento de primera línea para los pacientes con EPOC de grupo D(GOLD 2018). En noviembre de 2014, la Agencia Europea de Medicamentos aprobó una CDF de aclidinio 400 µg y formoterol 12 µg como Duaklir Genuair para los pacientes con EPOC. La evidencia de esta revisión surgió del metanálisis de seis ensayos con un estándar metodológico moderado a alto, lo que proporciona una mejor estimación de los efectos del tratamiento en los riesgos y beneficios del tratamiento combinado que cualquiera de los estudios solos. Uno de los estudios incluidos (D’Urzo 2017a) fue el estudio de prolongación del AUGMENT COPD, y solo se incluyeron los datos del estudio primario ya que el período de prolongación no fue una comparación verdaderamente aleatoria que tuvo una cantidad significativa de retiros. Los artículos publicados no informaron algunos de los datos necesarios para el metanálisis. Para obtenerlos se estableció contacto con los fabricantes quienes aceptaron aportar información adicional útil. La mayoría de los datos de los artículos publicados informaron la diferencia en los efectos del tratamiento versus las monoterapias o placebo en lugar de los brazos individuales. En consecuencia, se solicitaron los valores exactos y estos se obtuvieron para dos estudios (ACLIFORM COPD; AUGMENT COPD), o se utilizaron los datos proporcionados por el sitio web de ClinicalTrials o los datos a nivel del participante de la base de datos AztraZeneca para otros ensayos, para maximizar la exactitud de nuestra evidencia. Las características clínicas de los participantes inscritos en los ensayos, la gravedad inicial de la enfermedad y los fármacos previos fueron similares entre los brazos del ensayo. Hubo una heterogeneidad escasa o nula para la mayoría de las estimaciones de resumen, salvo para la cantidad total de muertes en comparación con aclidinio ya que hubo más muertes en el grupo de CDF; sin embargo, ninguno de estos factores se consideró relacionado con la medicación del estudio, debido a que todos estos participantes tenían varias comorbilidades subyacentes. En la mayoría de los estudios, el formoterol se administró con el inhalador Genuair para mantener el cegamiento (este dispositivo no es el ideal y podría afectar las medidas de resultado para la comparación con formoterol). En esta revisión, se realizó el análisis de subgrupos de la dosis de formoterol con la CDF, 12 µg o 6 µg, para la mayoría de los resultados; sin embargo, no hubo evidencia de diferencias entre los subgrupos.

En general, la evidencia de esta revisión respaldó la eficacia del tratamiento combinado, en comparación con las monoterapias y el placebo, para mejorar la función pulmonar y reducir la disnea en pacientes con EPOC estable, lo que está en conformidad con las recomendaciones GOLD actualizadas (GOLD 2018). En función de la evidencia de esta revisión, el tratamiento combinado de aclidinio/formoterol no reveló ninguna diferencia en la disminución de las exacerbaciones, ya sean las exacerbaciones moderadas que requirieron un ciclo corto de esteroides o de antibióticos, o ambos, o las exacerbaciones graves que requirieron ingresos hospitalarios. Hubo una posibilidad de una mayor reducción en las exacerbaciones moderadas que requirieron la administración de esteroides o de antibióticos, o ambos, con CDF en comparación con formoterol, aunque los cálculos resumidos tal vez no sean clínicamente significativos. Esto podría deberse al efecto en la potencia y a que el análisis incluyó tres ensayos con más participantes. Para otras comparaciones, los datos que contribuyen con el resultado de exacerbación provinieron solamente de dos ensayos de 24 semanas de duración y se cree firmemente que incluir estudios adicionales más prolongados alterará esta evidencia. No hubo diferencias en la mortalidad por todas las causas, los eventos adversos ni los EAG no mortales que indicaran la seguridad de este tratamiento combinado. Hubo una cantidad estadísticamente menor de eventos adversos con CDF de aclidinio/formoterol en comparación con formoterol solo. En general, la evidencia de esta revisión indica que el tratamiento combinado fue una opción eficaz y segura para tratar a los pacientes con EPOC estable.

Calidad de la evidencia

Se evaluó la calidad de la evidencia de los resultados de la revisión con la evaluación GRADE (tabla 1 Resumen de los resultados; tabla 2 Resumen de los resultados. tabla 3 Resumen de los resultados), que varió de baja a alta. Los siete estudios incluidos en esta revisión fueron patrocinados por la industria farmacéutica y se realizaron según protocolos prestablecidos similares y en general tuvieron una escasa posibilidad de sesgo importante. Dos ensayos aportaron los metanálisis de la mayoría de los resultados de esta revisión (ACLIFORM COPD; AUGMENT COPD), y, ocasionalmente, también lo hicieron otros cuatro ensayos. Los estudios que aportaron datos para esta revisión eran amplios y se consideró que tenían un riesgo de sesgo bajo o incierto. Todas las comparaciones de los resultados eran directas y no hubo una heterogeneidad importante en la mayoría de los resultados. En casos excepcionales de comparación con formoterol solo, resultó difícil explicar la heterogeneidad estadística moderada, los estudios tuvieron los mismos criterios de inclusión y de exclusión e inscribieron a participantes con una gravedad de la enfermedad similar y utilizaron abordajes estadísticos y metodológicos similares. La mayoría de las estimaciones del efecto agrupadas no fueron precisas, lo que motivó la disminución de la calificación de la evidencia en nuestra revisión. La mejoría en los síntomas y en la función pulmonar se calificó como evidencia de certeza alta para todas las comparaciones y tenemos confianza en que el verdadero efecto se encuentra cerca de la estimación del efecto. Se estimó que la certeza de la evidencia para la mejoría en la puntuación total del SGRQ era alta para la comparación de CDF de aclidinio/formoterol con placebo, moderada para aclidinio y baja para formoterol. En los estudios primarios, algunos criterios de valoración predefinidos, especialmente las exacerbaciones, no se publicaron específicamente como exacerbaciones moderadas y graves, aunque estos resultados de interés fueron proporcionados por el fabricante. Sin embargo, se tiene menos confianza y certeza sobre los resultados de exacerbaciones e ingresos hospitalarios para todas las comparaciones. Como se trata de eventos relativamente poco frecuentes para los ensayos actualmente incluidos de duración relativamente corta, la información adicional de los futuros ensayos podría modificar la confianza en estos resultados y aportar nueva evidencia para la práctica clínica.

Sesgos potenciales en el proceso de revisión

Se hizo el máximo esfuerzo por obtener literatura gris para disminuir el sesgo durante el proceso de revisión. Además de la búsqueda electrónica sistemática del Grupo Cochrane de Vías Respiratorias, se realizó una búsqueda exhaustiva de otras fuentes como los sitios web del fabricante y los registros del ensayo. También se estableció contacto con los autores del ensayo en relación con los datos faltantes y se obtuvo acceso a los datos a nivel del participante de los ensayos individuales en cuestión. Dos autores de revisión determinaron la inclusión y la exclusión de forma independiente, extrajeron los datos y determinaron el riesgo de sesgo para reducir el error. La mayoría de los datos fueron coherentes en todos los ensayos publicados y en el sitio web ClinicalTrial.gov, excepto el resultado de los pacientes que respondieron el SGRQ en ACLIFORM COPD. Se observó una incoherencia en el informe sobre los pacientes que respondieron el SGRQ, ya que la cantidad de pacientes que respondieron no parecía ser compatible con el hallazgo de mejoría global en la puntuación total del SGRQ para los brazo de formoterol y de CDF de aclidinio/formoterol. El hecho de que esta revisión solo incluyera siete estudios limitó el uso de un gráfico en embudo para realizar una evaluación adecuada del sesgo de publicación.

La mayoría de los datos informados se obtuvieron a partir de ECA con una metodología robusta y, en general, se considera que la posibilidad de introducción de sesgos sistemáticos importantes en estos ensayos es baja. Las características clínicas de los participantes inscritos en los ensayos y la gravedad de la enfermedad inicial fueron similares en los ensayos. En general, las tasas de abandono fueron de 10% a 20%, con tasas mayores en AUGMENT COPD y en Donohue 2016. En AUGMENT COPD y en Donohue 2016 hubo una pérdida ligeramente mayor de participantes en los brazos de placebo que en los brazos experimentales. Tanto los brazos con CDF de aclidinio/formoterol como de formoterol solo tuvieron tasas de abandonos altas. Las pérdidas durante el seguimiento se debieron, con mayor frecuencia, al efecto terapéutico insatisfactorio, o a los eventos adversos, o al retiro del consentimiento. Por lo tanto, es posible que la discrepancia entre el abandono en los brazos de placebo y experimentales haya introducido cierto grado de sesgo, y es muy probable que este sesgo produjera una subestimación de los efectos del tratamiento de CDF. Sin embargo, la repercusión general de dicho sesgo probablemente fue baja ya que los análisis se basaron en la población de intención de tratar.

El uso concomitante de ICS y metilxantinas puede afectar los resultados; sin embargo, haber incluido solamente a participantes que ya habían logrado un estado estable con estos fármacos, durante al menos cuatro semanas antes de la selección, podría tener escasa influencia en las estimaciones globales del efecto. Esto también es respaldado por los hallazgos de un análisis de subgrupos de datos agrupados de ACLIFORM COPD y AUGMENT COPD, según el consumo concomitante de ICS, en los cuales aclidinio/formoterol 400/12 µg mejoró la función pulmonar en comparación con placebo y las monoterapias, de forma independiente de la administración de ICS (D'Urzo 2017b). Además, el consumo previo de ABAP, AMAP, ICS o combinaciones de cualquiera de estos fármacos también podría introducir sesgo; sin embargo, no se observó ninguna diferencia evidente en las proporciones de participantes tratados con alguno de estos agentes en los brazos de intervención y de control de los estudios incluidos. En consecuencia, se asume que no habrá un cambio significativo en los hallazgos de esta revisión.

Acuerdos y desacuerdos con otros estudios o revisiones

Hay cada vez más evidencia sobre la mayor eficacia del tratamiento combinado de ABAP/AMAP en comparación con otras monoterapias o con placebo en la mejoría de los síntomas, la función pulmonar y la calidad de vida, además de la disminución de las exacerbaciones. Hasta la fecha, a pesar de la gran cantidad de metanálisis y revisiones sistemáticas sobre el tratamiento combinado de ABAP/AMAP, los estudios que abordan específicamente el aclidinio y el formoterol son escasos. En una revisión sistemática de una comparación indirecta entre aclidinio/formoterol y tiotropio (Medic 2016), el tratamiento combinado fue más eficaz que el tiotropio solo para mejorar el VEM1 y la disnea con una cantidad correspondiente mayor de pacientes que respondieron según el TDI. No hubo diferencias en la calidad de vida, las hospitalizaciones, los eventos adversos y los EAG. Bateman 2015 y Di Marco 2017 informaron que el tratamiento con CDF de aclidinio/formoterol 400/12 μg mejoró en forma significativa el TDI focal en comparación con las monoterapias y el placebo, con la posibilidad de controlar los síntomas durante las 24 horas, este hallazgo fue similar al de este estudio. Esa revisión también reveló una disminución significativa de las exacerbaciones moderadas a graves versus placebo, pero no frente a las monoterapias, un resultado que esta revisión no demostró. Los hallazgos de esta revisión sobre la mejoría del VEM1 y la disminución de la disnea por parte de la CDF de aclidinio/formoterol también respalda las guías GOLD actualizadas en 2018 (GOLD 2018).

La evidencia actual indica que el tratamiento con ABAP/AMAP fue más eficaz que la monoterapia en cuanto a los síntomas, la calidad de vida y la función pulmonar (Calzetta 2017a; Lal 2017; Oba 2016; Rodrigo 2017), si bien esta revisión no reveló una mejoría en la CdVRS versus aclidinio. En otro metanálisis, las combinaciones de ABAP/AMAP fueron significativamente más eficaces que ABAP o AMAP solos, en cuanto a la mejoría en el tiempo de resistencia y la capacidad inspiratoria (Calzetta 2017b), aunque no se incluyeron ciertos estudios, sobre todo los que compararon CDF de aclidinio/formoterol con monoterapia. En esta revisión, los pacientes que se trataron con CDF de aclidinio/formoterol tuvieron menos exacerbaciones que requirieron esteroides o antibióticos, o ambos, que con formoterol solo; pero esto no fue así cuando se comparó con aclidinio solo, que es un hallazgo comparable como en el metanálisis en red de Oba 2016. El grado variable de síntomas durante el momento inicial podría afectar los hallazgos de la función pulmonar y la mejoría sintomática; sin embargo, las características iniciales de los participantes en los grupos son similares. Un análisis agrupado a posteriori ACLIFORM COPD y AUGMENT COPD clasificado según el estado del síntoma demostró una magnitud similar de las mejorías en el VEM1 posterior a la dosis, de manera independiente de los síntomas iniciales. Como es de esperar, se observó una mejoría mayor en el VEM1 respecto del período inicial y se observaron casos de disnea en más participantes sintomáticos(Miravitlles 2016). Según los estudios a largo plazo, con una duración de cinco años, realizados en Escocia (Ramos 2016) y en España (Capel 2018), el tratamiento combinado de CDF de aclidinio/formoterol 400/12 μg puede considerarse una opción costo‐efectiva en comparación con aclidinio 400 μg solo o de tiotropio/olodaterol en pacientes con EPOC moderada a grave, aunque esta revisión no evaluó el costo de estos medicamentos.

Study flow diagram.
Figuras y tablas -
Figure 1

Study flow diagram.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Forest plot of comparison: 1 Fixed‐dose combination (FDC) aclidinium and formoterol versus aclidinium, Outcome: 1.7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score.
Figuras y tablas -
Figure 3

Forest plot of comparison: 1 Fixed‐dose combination (FDC) aclidinium and formoterol versus aclidinium, Outcome: 1.7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score.

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Forest plot of comparison: 1 Fixed‐dose combination (FDC) aclidinium and formoterol versus aclidinium, Outcome: 1.11 Number of participants with adverse events (not including serious adverse events).
Figuras y tablas -
Figure 4

Forest plot of comparison: 1 Fixed‐dose combination (FDC) aclidinium and formoterol versus aclidinium, Outcome: 1.11 Number of participants with adverse events (not including serious adverse events).

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Forest plot of comparison: 2 Fixed‐dose combination (FDC) aclidinium and formoterol versus formoterol, Outcome: 2.1 Number of participants with exacerbations requiring steroids or antibiotics or both.
Figuras y tablas -
Figure 5

Forest plot of comparison: 2 Fixed‐dose combination (FDC) aclidinium and formoterol versus formoterol, Outcome: 2.1 Number of participants with exacerbations requiring steroids or antibiotics or both.

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Forest plot of comparison: 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome: 3.2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score.
Figuras y tablas -
Figure 6

Forest plot of comparison: 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome: 3.2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score.

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 1 Exacerbations requiring steroids or antibiotics or both: number of participants.
Figuras y tablas -
Analysis 1.1

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 1 Exacerbations requiring steroids or antibiotics or both: number of participants.

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score.
Figuras y tablas -
Analysis 1.2

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score.

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 3 Quality of life: number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score.
Figuras y tablas -
Analysis 1.3

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 3 Quality of life: number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score.

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 4 Non‐fatal serious adverse events.
Figuras y tablas -
Analysis 1.4

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 4 Non‐fatal serious adverse events.

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 5 Total number of deaths.
Figuras y tablas -
Analysis 1.5

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 5 Total number of deaths.

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 6 Hospital admissions due to exacerbations: number of participants.
Figuras y tablas -
Analysis 1.6

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 6 Hospital admissions due to exacerbations: number of participants.

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score.
Figuras y tablas -
Analysis 1.7

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score.

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 8 Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit).
Figuras y tablas -
Analysis 1.8

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 8 Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit).

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 9 Change in lung function: from baseline in trough forced expiratory volume in 1 second (FEV1) (L).
Figuras y tablas -
Analysis 1.9

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 9 Change in lung function: from baseline in trough forced expiratory volume in 1 second (FEV1) (L).

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 10 Change in lung function: from baseline in 1‐hour postmorning dose FEV1 (L).
Figuras y tablas -
Analysis 1.10

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 10 Change in lung function: from baseline in 1‐hour postmorning dose FEV1 (L).

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Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 11 Adverse events (not including serious adverse events): number of participants.
Figuras y tablas -
Analysis 1.11

Comparison 1 Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium, Outcome 11 Adverse events (not including serious adverse events): number of participants.

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 1 Exacerbations requiring steroids or antibiotics or both: number of participants.
Figuras y tablas -
Analysis 2.1

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 1 Exacerbations requiring steroids or antibiotics or both: number of participants.

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score.
Figuras y tablas -
Analysis 2.2

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score.

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 3 Quality of life: Number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score.
Figuras y tablas -
Analysis 2.3

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 3 Quality of life: Number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score.

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 4 Non‐fatal serious adverse events.
Figuras y tablas -
Analysis 2.4

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 4 Non‐fatal serious adverse events.

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 5 Total number of deaths.
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Analysis 2.5

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 5 Total number of deaths.

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 6 Hospital admissions due to exacerbations: number of participants.
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Analysis 2.6

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 6 Hospital admissions due to exacerbations: number of participants.

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score.
Figuras y tablas -
Analysis 2.7

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score.

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 8 Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit).
Figuras y tablas -
Analysis 2.8

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 8 Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit).

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 9 Change in lung function: from baseline in trough forced expiratory volume in 1 second (FEV1) (L).
Figuras y tablas -
Analysis 2.9

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 9 Change in lung function: from baseline in trough forced expiratory volume in 1 second (FEV1) (L).

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 10 Change lung function: from baseline in 1‐hour postmorning dose FEV1 (L).
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Analysis 2.10

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 10 Change lung function: from baseline in 1‐hour postmorning dose FEV1 (L).

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Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 11 Adverse events (not including serious adverse events): number of participants.
Figuras y tablas -
Analysis 2.11

Comparison 2 Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol, Outcome 11 Adverse events (not including serious adverse events): number of participants.

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 1 Exacerbations requiring steroids or antibiotics or both: number of participants.
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Analysis 3.1

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 1 Exacerbations requiring steroids or antibiotics or both: number of participants.

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score.
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Analysis 3.2

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score.

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 3 Quality of life: Number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score.
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Analysis 3.3

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 3 Quality of life: Number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score.

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 4 Non‐fatal serious adverse events.
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Analysis 3.4

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 4 Non‐fatal serious adverse events.

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 5 Total number of deaths.
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Analysis 3.5

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 5 Total number of deaths.

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 6 Hospital admissions due to exacerbations: number of participants.
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Analysis 3.6

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 6 Hospital admissions due to exacerbations: number of participants.

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score.
Figuras y tablas -
Analysis 3.7

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score.

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 8 Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit).
Figuras y tablas -
Analysis 3.8

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 8 Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit).

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 9 Change in lung function: from baseline in trough forced expiratory volume in 1 second (FEV1) (L).
Figuras y tablas -
Analysis 3.9

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 9 Change in lung function: from baseline in trough forced expiratory volume in 1 second (FEV1) (L).

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 10 Change lung function: from baseline in 1‐hour postmorning dose FEV1 (L).
Figuras y tablas -
Analysis 3.10

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 10 Change lung function: from baseline in 1‐hour postmorning dose FEV1 (L).

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Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 11 Adverse events (not including serious adverse events): number of participants.
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Analysis 3.11

Comparison 3 Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo, Outcome 11 Adverse events (not including serious adverse events): number of participants.

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Summary of findings for the main comparison. Fixed‐dose combination aclidinium/formoterol compared to aclidinium alone for chronic obstructive pulmonary disease (COPD)

Fixed‐dose combination aclidinium/formoterol compared to aclidinium for chronic obstructive pulmonary disease (COPD)

Patient or population: people with COPD
Setting: community
Intervention: FDC aclidinium/formoterol
Comparison: aclidinium

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with aclidinium

Risk with FDC aclidinium/formoterol

Exacerbations requiring steroids or antibiotics or both: number of participants
Follow‐up: 24 weeks

105 per 1000

101 per 1000
(77 to 130)

OR 0.95
(0.71 to 1.27)

2156
(2 RCTs)

⊕⊕⊕⊝
Moderatea

—

Quality of life: number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score
Follow‐up: 24 weeks

541 per 1000

579 per 1000
(533 to 624)

OR 1.17
(0.97 to 1.41)

2002
(2 RCTs)

⊕⊕⊕⊝
Moderatea

The mean quality of life: change from baseline in SGRQ total score was 0.92 lower (2.15 lower to 0.3 higher) in FDC group (2002 participants, 2 RCTs)

Non‐fatal serious adverse events
Follow‐up: 4–24 weeks

41 per 1000

49 per 1000
(33 to 72)

OR 1.19
(0.79 to 1.80)

2473
(3 RCTs)

⊕⊕⊕⊝
Moderatea

—

Hospital admissions due to exacerbations: number of participants
Follow‐up: 24 weeks

18 per 1000

11 per 1000
(5 to 23)

OR 0.62
(0.29 to 1.29)

2156
(2 RCTs)

⊕⊕⊕⊝
Moderatea

—

Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit)
Follow‐up: 24 weeks

557 per 1000

627 per 1000
(582 to 671)

OR 1.34
(1.11 to 1.62)

2013
(2 RCTs)

⊕⊕⊕⊕
High

The mean improvement in symptoms: change from baseline in TDI focal score was 0.37 higher (0.07 higher to 0.68 higher) in FDC group (2013 participants, 2 RCTs).

Change in lung function: from baseline in trough FEV1 (L)
Follow‐up: 4–24 weeks

Mean change from baseline in trough FEV1 (L) across aclidinium group ranged from –0.017 to 0.066

Mean change from baseline in trough FEV1 (L) in the FDC group was 0.02 higher (0 to 0.04 higher)

—

2333
(3 RCTs)

⊕⊕⊕⊕
High

—

Adverse events (not including serious adverse events): number of participants

Follow‐up: 4–24 weeks

194 per 1000

186 per 1000
(155 to 221)

OR 0.95
(0.76 to 1.18)

2473
(3 RCTs)

⊕⊕⊕⊝
Moderatea

—

*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).

CI: confidence interval; COPD: chronic obstructive pulmonary disease; FDC: fixed‐dose combination; FEV1: forced expiratory volume in 1 second; OR: odds ratio; RCT: randomised controlled trial; SGRQ: St George's Respiratory Questionnaire; TDI: Transitional Dyspnoea Index.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for serious imprecision: the CIs included a potential for appreciable benefit or harm.

Figuras y tablas -
Summary of findings for the main comparison. Fixed‐dose combination aclidinium/formoterol compared to aclidinium alone for chronic obstructive pulmonary disease (COPD)
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Summary of findings 2. Fixed‐dose combination aclidinium/formoterol compared to formoterol for chronic obstructive pulmonary disease (COPD)

Fixed‐dose combination aclidinium/ formoterol compared to formoterol for chronic obstructive pulmonary disease (COPD)

Patient or population: people with COPD
Setting: community
Intervention: FDC aclidinium/formoterol
Comparison: formoterol

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with formoterol

Risk with FDC aclidinium/formoterol

Exacerbations requiring steroids or antibiotics or both: number of participants
Follow‐up: 24 weeks

154 per 1000

124 per 1000
(101 to 152)

OR 0.78
(0.62 to 0.99)

2694
(3 RCTs)

⊕⊕⊕⊕
High

—

Quality of life: number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score
Follow‐up: 24 weeks

524 per 1000

559 per 1000
(495 to 623)

OR 1.15
(0.89 to 1.50)

1000
(1 RCT)

⊕⊕⊝⊝
Lowa,b

The mean quality of life: change from baseline in SGRQ total score was 1.88 lower (3.1 lower to 0.65 lower) in FDC group (2002 participants, 2 RCTs).

Non‐fatal serious adverse events
Follow‐up: 4–52 weeks

50 per 1000

58 per 1000
(42 to 79)

OR 1.15
(0.82 to 1.61)

3140
(5 RCTs)

⊕⊕⊕⊝
Moderatea

—

Hospital admissions due to exacerbations: number of participants
Follow‐up: 24–52 weeks

27 per 1000

20 per 1000
(12 to 34)

OR 0.76
(0.45 to 1.28)

2694
(3 RCTs)

⊕⊕⊕⊝
Moderatea

—

Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit)
Follow‐up: 24 weeks

565 per 1000

628 per 1000
(582 to 670)

OR 1.30
(1.07 to 1.56)

2010
(2 RCTs)

⊕⊕⊕⊕
High

The mean improvement in symptoms: change from baseline in TDI focal score was 0.42 higher (0.11 higher to 0.72 higher) in FDC group (2010 participants, 2 RCTs).

Change in lung function: from baseline in trough FEV1 (L)
Follow‐up: 4–24 weeks

Mean change from baseline in trough FEV1 (L) across formoterol group ranged from –0.002 to 0.118

Mean change from baseline in trough FEV1 (L) in the FDC group was 0.04 higher (0.03 higher to 0.06 higher)

—

2411
(4 RCTs)

⊕⊕⊕⊕
High

—

Adverse events (not including serious adverse events): number of participants
Follow‐up: 4–52 weeks

271 per 1000

225 per 1000
(195 to 257)

OR 0.78
(0.65 to 0.93)

3140
(5 RCTs)

⊕⊕⊕⊕
High

—

*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).

CI: confidence interval; COPD: chronic obstructive pulmonary disease; FDC: fixed‐dose combination; FEV1: forced expiratory volume in 1 second; OR: odds ratio; RCT: randomised controlled trial; SGRQ: St George's Respiratory Questionnaire; TDI: Transitional Dyspnoea Index.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for serious imprecision: CIs included a potential for appreciable benefit or harm.

bDowngraded one level as ACLIFORM COPD did not report the SGRQ responders for formoterol arm in the published articles.

Figuras y tablas -
Summary of findings 2. Fixed‐dose combination aclidinium/formoterol compared to formoterol for chronic obstructive pulmonary disease (COPD)
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Summary of findings 3. Fixed‐dose combination aclidinium/formoterol compared to placebo for chronic obstructive pulmonary disease (COPD)

Fixed dose combination aclidinium/formoterol compared to placebo for chronic obstructive pulmonary disease (COPD)

Patient or population: people with chronic obstructive pulmonary disease (COPD)
Setting: community
Intervention: FDC aclidinium/formoterol
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with FDC aclidinium/formoterol

Exacerbations requiring steroids or antibiotics or both: number of participants
Follow‐up: 24 weeks

129 per 1000

109 per 1000
(82 to 143)

OR 0.82
(0.60 to 1.12)

1960
(2 RCTs)

⊕⊕⊕⊝
Moderatea

—

Quality of life: number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score
Follow‐up: 24 weeks

433 per 1000

568 per 1000
(515 to 619)

OR 1.72
(1.39 to 2.13)

1823
(2 RCTs)

⊕⊕⊕⊕
High

The mean quality of life: change from baseline in SGRQ total score was 2.91 lower (4.33 lower to 1.5 lower) in FDC group (1823 participants, 2 RCTs).

Non‐fatal serious adverse events
Follow‐up: 4–24 weeks

38 per 1000

42 per 1000
(27 to 64)

OR 1.12
(0.72 to 1.74)

2527
(4 RCTs)

⊕⊕⊕⊝
Moderatea

—

Hospital admissions due to exacerbations: number of participants
Follow‐up: 24 weeks

21 per 1000

12 per 1000
(5 to 25)

OR 0.55
(0.25 to 1.18)

1960
(2 RCTs)

⊕⊕⊕⊝
Moderatea

—

Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit)
Follow‐up: 24 weeks

394 per 1000

620 per 1000
(568 to 669)

OR 2.51
(2.02 to 3.11)

1832
(2 RCTs)

⊕⊕⊕⊕
High

The mean improvement in symptoms: change from baseline in TDI focal score was 1.32 higher (0.96 higher to 1.69 higher) in FDC group (1832 participants, 2 RCTs).

Change in lung function: from baseline in trough FEV1 (L)
Follow‐up: 4–24 weeks

Mean change from baseline in trough FEV1 (L) across placebo group ranged from –0.061 to –0.031

Mean change from baseline in trough FEV1 (L) in the FDC group was 0.12 higher (0.10 higher to 0.14 higher)

—

2137
(3 RCTs)

⊕⊕⊕⊕
High

—

Adverse events (not including serious adverse events): number of participants
Follow‐up: 4–24 weeks

175 per 1000

171 per 1000
(139 to 206)

OR 0.97
(0.76 to 1.22)

2527
(4 RCTs)

⊕⊕⊕⊝
Moderatea

—

*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).

CI: confidence interval; COPD: chronic obstructive pulmonary disease; FDC: fixed‐dose combination; FEV1: forced expiratory volume in 1 second; OR: odds ratio; RCT: randomised controlled trial; SGRQ: St George's Respiratory Questionnaire; TDI: Transitional Dyspnoea Index.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for serious imprecision: the CIs included a potential for appreciable benefit or harm.

Figuras y tablas -
Summary of findings 3. Fixed‐dose combination aclidinium/formoterol compared to placebo for chronic obstructive pulmonary disease (COPD)
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Table 1. Overview of included studies

Study

Duration of study

Number randomised

Intervention

Comparison

ACLIFORM COPD

24 weeks

1729

Inhaled FDC aclidinium/formoterol 400/6 μg twice daily

Inhaled FDC aclidinium/formoterol 400/12 μg twice daily

Inhaled aclidinium 400 μg twice daily

Inhaled formoterol 12 μg twice daily

Inhaled placebo twice daily

ACTIVATE

8 weeks

267

Inhaled FDC aclidinium/formoterol 400/12 μg twice daily

Inhaled placebo twice daily

AUGMENT COPD

24 weeks

1692

Inhaled FDC aclidinium/formoterol 400/6 μg twice daily

Inhaled FDC aclidinium/formoterol 400/12 μg twice daily

Inhaled aclidinium 400 μg twice daily

Inhaled formoterol 12 μg twice daily

Inhaled placebo twice daily

D'Urzo 2017a

(extension study of AUGMENT COPD)

28 weeks

921

Inhaled FDC aclidinium/formoterol 400/6 μg twice daily

Inhaled FDC aclidinium/formoterol 400/12 μg twice daily

Inhaled aclidinium 400 μg twice daily

Inhaled formoterol 12 μg twice daily

Inhaled placebo twice daily

Donohue 2016

52 weeks

590

Inhaled FDC aclidinium/formoterol 400/12 μg twice daily

Inhaled formoterol 12 μg twice daily

NCT00706914

4 weeks

156

Inhaled FDC aclidinium/formoterol 200/12 μg once daily in the morning and placebo once daily in the evening

Inhaled FDC aclidinium/formoterol 200/12 μg once daily in the morning and formoterol 12 μg once daily in the evening

Inhaled formoterol 12 μg twice daily

Sliwinski 2010

4 weeks

566

Inhaled FDC aclidinium/formoterol 400/6 μg once daily

Inhaled FDC aclidinium/formoterol 400/12 μg once daily

Inhaled FDC aclidinium/formoterol 400/18 μg once daily

Inhaled aclidinium 200 μg once daily

Inhaled formoterol 12 μg once daily

Inhaled placebo once daily

FDC: fixed‐dose combination.
Figuras y tablas -
Table 1. Overview of included studies
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Comparison 1. Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Exacerbations requiring steroids or antibiotics or both: number of participants Show forest plot

2

2156

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.71, 1.27]

1.1 Formoterol 12 μg

2

1080

Odds Ratio (M‐H, Fixed, 95% CI)

0.91 [0.60, 1.39]

1.2 Formoterol 6 μg

2

1076

Odds Ratio (M‐H, Fixed, 95% CI)

0.99 [0.65, 1.49]

2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score Show forest plot

2

2002

Mean Difference (IV, Fixed, 95% CI)

‐0.92 [‐2.15, 0.30]

2.1 Formoterol 12 μg

2

1004

Mean Difference (IV, Fixed, 95% CI)

‐0.77 [‐2.51, 0.96]

2.2 Formoterol 6 μg

2

998

Mean Difference (IV, Fixed, 95% CI)

‐1.08 [‐2.81, 0.65]

3 Quality of life: number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score Show forest plot

2

2002

Odds Ratio (M‐H, Fixed, 95% CI)

1.17 [0.97, 1.41]

3.1 Formoterol 12 μg

2

1004

Odds Ratio (M‐H, Fixed, 95% CI)

1.12 [0.86, 1.45]

3.2 Formoterol 6 μg

2

998

Odds Ratio (M‐H, Fixed, 95% CI)

1.22 [0.93, 1.59]

4 Non‐fatal serious adverse events Show forest plot

3

2473

Odds Ratio (M‐H, Fixed, 95% CI)

1.19 [0.79, 1.80]

4.1 Formoterol 12 μg

3

1238

Odds Ratio (M‐H, Fixed, 95% CI)

1.32 [0.74, 2.36]

4.2 Formoterol 6 μg

3

1235

Odds Ratio (M‐H, Fixed, 95% CI)

1.07 [0.60, 1.92]

5 Total number of deaths Show forest plot

3

2473

Peto Odds Ratio (Peto, Fixed, 95% CI)

0.66 [0.14, 3.16]

6 Hospital admissions due to exacerbations: number of participants Show forest plot

2

2156

Odds Ratio (M‐H, Fixed, 95% CI)

0.62 [0.29, 1.29]

6.1 Formoterol 12 μg

2

1080

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.19, 1.74]

6.2 Formoterol 6 μg

2

1076

Odds Ratio (M‐H, Fixed, 95% CI)

0.65 [0.24, 1.75]

7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score Show forest plot

2

2013

Mean Difference (IV, Fixed, 95% CI)

0.37 [0.07, 0.68]

7.1 Formoterol 12 μg

2

1012

Mean Difference (IV, Fixed, 95% CI)

0.42 [‐0.01, 0.85]

7.2 Formoterol 6 μg

2

1001

Mean Difference (IV, Fixed, 95% CI)

0.33 [‐0.10, 0.76]

8 Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit) Show forest plot

2

2013

Odds Ratio (M‐H, Fixed, 95% CI)

1.34 [1.11, 1.62]

8.1 Formoterol 12 μg

2

1012

Odds Ratio (M‐H, Fixed, 95% CI)

1.28 [0.98, 1.67]

8.2 Formoterol 6 μg

2

1001

Odds Ratio (M‐H, Fixed, 95% CI)

1.40 [1.08, 1.84]

9 Change in lung function: from baseline in trough forced expiratory volume in 1 second (FEV1) (L) Show forest plot

3

2333

Mean Difference (IV, Fixed, 95% CI)

0.02 [0.00, 0.04]

9.1 Formoterol 12 μg

3

1171

Mean Difference (IV, Fixed, 95% CI)

0.04 [0.01, 0.06]

9.2 Formoterol 6 μg

3

1162

Mean Difference (IV, Fixed, 95% CI)

0.01 [‐0.02, 0.04]

10 Change in lung function: from baseline in 1‐hour postmorning dose FEV1 (L) Show forest plot

2

2018

Mean Difference (IV, Fixed, 95% CI)

0.10 [0.08, 0.12]

10.1 Formoterol 12 μg

2

1013

Mean Difference (IV, Fixed, 95% CI)

0.12 [0.09, 0.15]

10.2 Formoterol 6 μg

2

1005

Mean Difference (IV, Fixed, 95% CI)

0.08 [0.05, 0.11]

11 Adverse events (not including serious adverse events): number of participants Show forest plot

3

2473

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.76, 1.18]

11.1 Formoterol 12 μg

3

1238

Odds Ratio (M‐H, Fixed, 95% CI)

0.93 [0.68, 1.27]

11.2 Formoterol 6 μg

3

1235

Odds Ratio (M‐H, Fixed, 95% CI)

0.97 [0.71, 1.31]
Figuras y tablas -
Comparison 1. Fixed‐dose combination (FDC) aclidinium/formoterol versus aclidinium
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Comparison 2. Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Exacerbations requiring steroids or antibiotics or both: number of participants Show forest plot

3

2694

Odds Ratio (M‐H, Fixed, 95% CI)

0.78 [0.62, 0.99]

1.1 Formoterol 12 μg

3

1622

Odds Ratio (M‐H, Fixed, 95% CI)

0.75 [0.56, 1.00]

1.2 Formoterol 6 μg

2

1072

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.57, 1.26]

2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score Show forest plot

2

2002

Mean Difference (IV, Fixed, 95% CI)

‐1.88 [‐3.10, ‐0.65]

2.1 Formoterol 12 μg

2

1005

Mean Difference (IV, Fixed, 95% CI)

‐1.72 [‐3.45, 0.02]

2.2 Formoterol 6 μg

2

997

Mean Difference (IV, Fixed, 95% CI)

‐2.03 [‐3.76, ‐0.30]

3 Quality of life: Number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score Show forest plot

1

1000

Odds Ratio (M‐H, Fixed, 95% CI)

1.15 [0.89, 1.50]

3.1 Formoterol 12 μg

1

501

Odds Ratio (M‐H, Fixed, 95% CI)

1.26 [0.87, 1.84]

3.2 Formoterol 6 μg

1

499

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.73, 1.53]

4 Non‐fatal serious adverse events Show forest plot

5

3140

Odds Ratio (M‐H, Fixed, 95% CI)

1.15 [0.82, 1.61]

4.1 Formoterol 12 μg

5

1914

Odds Ratio (M‐H, Fixed, 95% CI)

1.13 [0.76, 1.70]

4.2 Formoterol 6 μg

3

1226

Odds Ratio (M‐H, Fixed, 95% CI)

1.20 [0.65, 2.20]

5 Total number of deaths Show forest plot

5

3140

Peto Odds Ratio (Peto, Fixed, 95% CI)

1.46 [0.44, 4.87]

6 Hospital admissions due to exacerbations: number of participants Show forest plot

3

2694

Odds Ratio (M‐H, Fixed, 95% CI)

0.76 [0.45, 1.28]

6.1 Formoterol 12 μg

3

1622

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.38, 1.25]

6.2 Formoterol 6 μg

2

1072

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.34, 3.28]

7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score Show forest plot

2

2010

Mean Difference (IV, Fixed, 95% CI)

0.42 [0.11, 0.72]

7.1 Formoterol 12 μg

2

1011

Mean Difference (IV, Fixed, 95% CI)

0.47 [0.03, 0.90]

7.2 Formoterol 6 μg

2

999

Mean Difference (IV, Fixed, 95% CI)

0.37 [‐0.06, 0.80]

8 Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit) Show forest plot

2

2010

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [1.07, 1.56]

8.1 Formoterol 12 μg

2

1011

Odds Ratio (M‐H, Fixed, 95% CI)

1.23 [0.94, 1.60]

8.2 Formoterol 6 μg

2

999

Odds Ratio (M‐H, Fixed, 95% CI)

1.37 [1.05, 1.79]

9 Change in lung function: from baseline in trough forced expiratory volume in 1 second (FEV1) (L) Show forest plot

4

2411

Mean Difference (IV, Fixed, 95% CI)

0.04 [0.03, 0.06]

9.1 Formoterol 12 μg

4

1254

Mean Difference (IV, Fixed, 95% CI)

0.05 [0.03, 0.08]

9.2 Formoterol 6 μg

3

1157

Mean Difference (IV, Fixed, 95% CI)

0.04 [0.01, 0.07]

10 Change lung function: from baseline in 1‐hour postmorning dose FEV1 (L) Show forest plot

2

2021

Mean Difference (IV, Fixed, 95% CI)

0.09 [0.07, 0.11]

10.1 Formoterol 12 μg

2

1015

Mean Difference (IV, Fixed, 95% CI)

0.11 [0.08, 0.14]

10.2 Formoterol 6 μg

2

1006

Mean Difference (IV, Fixed, 95% CI)

0.07 [0.04, 0.10]

11 Adverse events (not including serious adverse events): number of participants Show forest plot

5

3140

Odds Ratio (M‐H, Fixed, 95% CI)

0.78 [0.65, 0.93]

11.1 Formoterol 12 μg

5

1914

Odds Ratio (M‐H, Fixed, 95% CI)

0.79 [0.63, 0.99]

11.2 Formoterol 6 μg

3

1226

Odds Ratio (M‐H, Fixed, 95% CI)

0.76 [0.56, 1.02]
Figuras y tablas -
Comparison 2. Fixed‐dose combination (FDC) aclidinium/formoterol versus formoterol
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Comparison 3. Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Exacerbations requiring steroids or antibiotics or both: number of participants Show forest plot

2

1960

Odds Ratio (M‐H, Fixed, 95% CI)

0.82 [0.60, 1.12]

1.1 Formoterol 12 μg

2

983

Odds Ratio (M‐H, Fixed, 95% CI)

0.82 [0.52, 1.28]

1.2 Formoterol 6 μg

2

977

Odds Ratio (M‐H, Fixed, 95% CI)

0.82 [0.53, 1.27]

2 Quality of life: change from baseline in St George's Respiratory Questionnaire (SGRQ) total score Show forest plot

2

1823

Mean Difference (IV, Fixed, 95% CI)

‐2.91 [‐4.33, ‐1.50]

2.1 Formoterol 12 μg

2

915

Mean Difference (IV, Fixed, 95% CI)

‐2.86 [‐4.87, ‐0.85]

2.2 Formoterol 6 μg

2

908

Mean Difference (IV, Fixed, 95% CI)

‐2.97 [‐4.97, ‐0.96]

3 Quality of life: Number of participants with clinically significant improvement (≥ 4 units) in SGRQ total score Show forest plot

2

1823

Odds Ratio (M‐H, Fixed, 95% CI)

1.72 [1.39, 2.13]

3.1 Formoterol 12 μg

2

915

Odds Ratio (M‐H, Fixed, 95% CI)

1.69 [1.26, 2.28]

3.2 Formoterol 6 μg

2

908

Odds Ratio (M‐H, Fixed, 95% CI)

1.75 [1.29, 2.36]

4 Non‐fatal serious adverse events Show forest plot

4

2527

Odds Ratio (M‐H, Fixed, 95% CI)

1.12 [0.72, 1.74]

4.1 Formoterol 12 μg

4

1399

Odds Ratio (M‐H, Fixed, 95% CI)

1.15 [0.63, 2.10]

4.2 Formoterol 6 μg

3

1128

Odds Ratio (M‐H, Fixed, 95% CI)

1.09 [0.56, 2.09]

5 Total number of deaths Show forest plot

3

2260

Peto Odds Ratio (Peto, Fixed, 95% CI)

3.79 [0.37, 39.13]

6 Hospital admissions due to exacerbations: number of participants Show forest plot

2

1960

Odds Ratio (M‐H, Fixed, 95% CI)

0.55 [0.25, 1.18]

6.1 Formoterol 12 μg

2

983

Odds Ratio (M‐H, Fixed, 95% CI)

0.49 [0.15, 1.60]

6.2 Formoterol 6 μg

2

977

Odds Ratio (M‐H, Fixed, 95% CI)

0.59 [0.21, 1.65]

7 Improvement in symptoms: change from baseline in Transitional Dyspnoea Index (TDI) focal score Show forest plot

2

1832

Mean Difference (IV, Fixed, 95% CI)

1.32 [0.96, 1.69]

7.1 Formoterol 12 μg

2

922

Mean Difference (IV, Fixed, 95% CI)

1.37 [0.85, 1.88]

7.2 Formoterol 6 μg

2

910

Mean Difference (IV, Fixed, 95% CI)

1.28 [0.77, 1.80]

8 Improvement in symptoms: number of participants with clinically significant improvement: using TDI focal score (≥ 1 unit) Show forest plot

2

1832

Odds Ratio (M‐H, Fixed, 95% CI)

2.51 [2.02, 3.11]

8.1 Formoterol 12 μg

2

922

Odds Ratio (M‐H, Fixed, 95% CI)

2.37 [1.75, 3.22]

8.2 Formoterol 6 μg

2

910

Odds Ratio (M‐H, Fixed, 95% CI)

2.65 [1.96, 3.60]

9 Change in lung function: from baseline in trough forced expiratory volume in 1 second (FEV1) (L) Show forest plot

3

2137

Mean Difference (IV, Fixed, 95% CI)

0.12 [0.10, 0.14]

9.1 Formoterol 12 μg

3

1073

Mean Difference (IV, Fixed, 95% CI)

0.13 [0.10, 0.16]

9.2 Formoterol 6 μg

3

1064

Mean Difference (IV, Fixed, 95% CI)

0.11 [0.07, 0.14]

10 Change lung function: from baseline in 1‐hour postmorning dose FEV1 (L) Show forest plot

2

1842

Mean Difference (IV, Fixed, 95% CI)

0.27 [0.25, 0.30]

10.1 Formoterol 12 μg

2

925

Mean Difference (IV, Fixed, 95% CI)

0.29 [0.25, 0.33]

10.2 Formoterol 6 μg

2

917

Mean Difference (IV, Fixed, 95% CI)

0.25 [0.22, 0.29]

11 Adverse events (not including serious adverse events): number of participants Show forest plot

4

2527

Odds Ratio (M‐H, Fixed, 95% CI)

0.97 [0.76, 1.22]

11.1 Formoterol 12 μg

4

1399

Odds Ratio (M‐H, Fixed, 95% CI)

0.89 [0.65, 1.22]

11.2 Formoterol 6 μg

3

1128

Odds Ratio (M‐H, Fixed, 95% CI)

1.07 [0.75, 1.53]
Figuras y tablas -
Comparison 3. Fixed‐dose combination (FDC) aclidinium and formoterol versus placebo
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