Clinically Important Deterioration (CID) and Ageing in COPD: A Systematic Review and Meta-Regression Analysis According to PRISMA Statement

Figures & data

Figure 1 PRISMA 2020 flow diagram for the identification of the studies included in the systematic review.

Notes: PRISMA figure adapted from Page MJ, McKenzie JE et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Creative Commons.²⁵

Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1 Main Characteristics of the Studies Included in the Systematic Review and Meta-Regression Analysis

Study, Year, PMID, and Reference	Number Identifier	Study Characteristics	Study Duration (Months)	Number of Analysed Patients	Drugs, Doses and Regimen of Administration	Main inclusion Criteria	Age (Years)	Male (%)	Current Smokers (%)	Smoking History (Pack-Years)	Baseline Post-Broncho-Dilator FEV1 (% Predicted)	AECOPD in the Previous Year (Rate)	Baseline SGRQ	Baseline CAT Score	Baseline mMRC Dyspnea Score	Jadad Score
Han et al 2021 33718490^Citation35	NCT02164513 (IMPACT)	Post-hoc analysis of the multicenter, randomized, double-blind, parallel-group, phase III IMPACT study	12.0	10,355	FF/UMEC/VI 100/62.5/25 μg QD vs FF/VI 100/25 μg QD vs UMEC/VI 62.5/25 μg QD	COPD, age >40 years, CAT score ≥10, FEV1 ≤50% of predicted AND ≥1 moderate or severe exacerbation in the previous year or FEV1 of ≥50–≤80% predicted AND ≥2 moderate or ≥1 severe exacerbation in the previous year	65.3	66.3	34.6	NA	45.6	NA	50.6	20.1	NA	5
Rabe et al 2021 33175291^Citation36	NCT01431274 (TONADO1); NCT01431287 (TONADO2)	Post-hoc analysis of the multicenter, randomized, double-blind, parallel-group, phase III replicate trials TONADO 1 and TONADO 2	12.0	2055	T/O 2.5/5 or 5/5 μg QD vs T 2.5 μg QD or 5 μg vs O 5 μg QD.	Moderate-to-very severe COPD (GOLD 2–4), age ≥40 years, smoking history of >10 pack-years	63.7	72.2	37.3	NA	49.5	NA	NA	NA	NA	5 (TONADO1); 5 (TONADO2)
Kerwin et al 2020 33061349^Citation37	NCT02347761 (GOLDEN 3); NCT02347774 (GOLDEN 4)	Post-hoc analysis of pooled data from the multicenter, randomized, double-blind, placebo-controlled phase III trials GOLDEN3 and GOLDEN4	3.0	1293	GLY 25 mcg and 50 mcg BID vs PCB	Moderate-to-very-severe COPD (post-bronchodilator, FEV1 ≤80% of predicted, FEV1 >0.7 L, and FEV1/FVC ratio <0.70), age ≥40 years, current or past smokers (≥10 pack-years)	63.2	56.0	52.9	NA	NA	NA	48.8	NA	NA	3 (GOLDEN 3); 3 (GOLDEN 4)
Rabe et al 2020 32646424^Citation38	NCT00144339	Post-hoc analysis of the multicenter, randomized, double-blind, parallel-group trial UPLIFT	48.0	5652	T 18 μg QD vs PCB	Moderate-to-very severe COPD (GOLD 2–4), age ≥40 years, smoking history of ≥10 pack-years	NA	NA	NA	NA	NA	NA	NA	NA	NA	5
Zheng et al 2020 32164675^Citation39	NCT01854645 (PINNACLE-1); NCT01854658 (PINNACLE-2); NCT02343458 (PINNACLE-4)	Post-hoc analysis of pooled data from the multicenter randomized, international, double-blind, placebo-controlled phase III trials PINNACLE-1, −2 and −4	6.0	4983	GLY/FOR 14.4/9.6 μg BID vs GLY 14.4 μg BID vs FOR 9.6 μg BID vs PCB	Moderate- to-very severe COPD according to ATS (post-bronchodilator, FEV1 <80% of predicted, and FEV1/FVC ratio <0.70), age >40 years, current or past smokers (≥10 pack-years)	63.3	61.9	50.7	49.2	NA	NA	44.0	17.3	1.8	5 (PINNACLE-1); 5 (PINNACLE-2); 4 (PINNACLE-4)
Chen et al 2020 32021143^Citation40	NCT02343458 (PINNACLE-4)	Chinese subgroup analysis of the multicenter randomized, double-blind, placebo-controlled, parallel-group Phase III trial PINNACLE-4	6.0	466	GLY/FOR 14.4/9.6 μg BID vs GLY 14.4 μg BID vs FOR 9.6 μg BID vs PCB	COPD according to ATS 2004, FEV1/FVC ratio <0.70 and FEV1 <80% predicted, age 40–80 years, smoking history of ≥10 pack-years	63.5	95.7	33.3	36.9	53.7	NA	34.1	11.8	NA	4
Bafadhel et al 2020 31924197^Citation41	NCT00206167 (SUN); NCT00206154 (SHINE); NCT00419744 (US3); NCT02157935 (RISE)	Post-hoc analysis of pooled data from the multicenter randomized, double-blind, double-dummy, parallel-group trials SUN, US3, SHINE and RISE	12.0 (SUN, US3); 6.0 (SHINE, RISE).	3576	BUD/FOR 160/4.5 μg BID vs FOR 4.5μg BID	COPD, age ≥40years, current or past smokers (≥10 pack-years), confirmed airflow obstruction, history of ≥1 exacerbation	63.2	61.3	42.3	NA	42.0	1.6	52.7	NA	NA	4 (SUN); 5 (SHINE); 5 (US3); 4 (RISE)
Maltais et al 2019 31666084^Citation42	NCT03034915 (EMAX)	Multicenter, randomized, double-blind, double-dummy, 3-arm parallel group EMAX study	6.0	2425	UMEC/VI 62.5/25 μg QD vs UMEC 62.5 μg QD vs SAL 50 μg BID	COPD (FEV1/FVC ratio <0.7), age ≥ 40 years, post- salbutamol FEV1 of ≥30–≤80% predicted, CAT score ≥10, ≤1 moderate exacerbation (requiring oral or systemic corticosteroids and/or antibiotics) and no severe exacerbations (requiring hospitalization) in the previous year	64.6	59.0	50.0	26.5	55.4	NA	44.7	19.2	NA	5
Singh et al 2019 30880943^Citation43	NCT01917331 (TRILOGY); NCT01911364 (TRINITY); NCT02579850 (TRIBUTE)	Post-hoc analysis of pooled data from the multicenter randomized, double-blind, active controlled, trial TRILOGY, the multicenter randomized, double-blind, double-dummy active controlled, parallel group trial TRINITY and the multicenter randomized, double-blind, double-dummy, active controlled, parallel group, phase IIIb Trial TRIBUTE	12.0	5588	TRILOGY: BDP/FOR/GLY 87/5/9 μg 2 inhalations BID vs BDP/FOR 87/5 μg 2 inhalations BID; TRINITY: BDP/FOR/GLY 87/5/9 μg 2 inhalations BID vs T 18 μg QD vs BDP/FOR 87/5 μg 2 inhalations BID + T 18 μg QD; TRIBUTE: BDP/FOR/GLY 87/5/9 μg 2 inhalations BID vs IND/GLY 85/43 μg QD	TRILOGY: age ≥40years, FEV1 of <50% predicted post-bronchodilator, FEV1/FVC <70%, at least one moderate or severe COPD exacerbation in the previous 12 months, use of ICS+LABA, ICS+LAMA, LABA+LAMA or LAMA at least 2 months before screening, CAT ≥10, BDI ≤10; TRINITY: age ≥40years, current or past smokers, FEV1 of <50% predicted post-bronchodilator, FEV1/FVC <70%, at least one moderate or severe COPD exacerbation in the previous 12 months, use of ICS+LABA, ICS+LAMA, LABA+LAMA or LAMA at least 2 months before screening, CAT ≥10. TRIBUTE: age ≥40years, current or past smokers, FEV1 of <50% predicted, post-bronchodilator FEV1/FVC <70%, at least one moderate or severe COPD exacerbation in the previous 12 months, use of ICS+LABA, ICS +LAMA, LABA+LAMA or LAMA at least 2 months before screening, CAT ≥10	63.6	75.0	46.7	NA	NA	1.2	51.7	21.3	NA	5 (TRILOGY); 5 (TRINITY); 5 (TRIBUTE)
Naya et al 2018 30191464^Citation44	NCT01772134 (AC4116135); NCT01772147 (AC4116136); NCT01957163 (200109); NCT02119286 (200110)	Post-hoc analysis of pooled data from the multicenter, randomized, double-blin, parallel-group, phase III trials AC4116135, AC4116136, 200109 and 200110	3.0	1637	AC4116135 and AC4116136: UMEC 62.5 μg QD + SAL/FP 500/50 μg BID vs PCB + SAL/FP 500/50 μg BID; 200109 and 200110: UMEC 62.5 μg QD + FF/VI 100/25 μg QD vs PCB + FF/VI 100/25 μg QD	COPD according to ATS 2004, age ≥40years, Group B or D according to GOLD 2016, current or past smokers (≥10 pack-years), mMRC grade≥2, FEV1 of ≤70% predicted post-bronchodilator, FEV1/FVC <70%	63.9	65.2	47.5	47.7	45.8	NA	44.6	NA	NA	5 (AC4116135); 5 (AC4116136); 5 (200109); 5 (200110)
Naya et al 2018 30302335^Citation6	NCT02345161 (FULFIL)	Post-hoc analysis of the multicenter, randomized, double-blind, double-dummy placebo-controlled parallel-group trial FULFIL	6.0	1810	FF/UMEC/VI 100/62.5/25 μg QD + PCB BID vs BUD/FOR 400/12 μg BID + PCB QD	COPD, age ≥40years, Group D according to GOLD 2015 (FEV1 <50% predicted and CAT ⩾10 or patients with FEV1 ⩾50% to <80% predicted and CAT ⩾10, and either at least two moderate exacerbations or at least one severe exacerbation in the past year)	63.9	74.1	43.9	39.3	45.3	NA	51.3	NA	NA	5
D’Urzo et al 2018 29795478^Citation45	NCT01005901 (GLOW1), NCT00929110 (GLOW2), NCT01613326 (GLOW5), NCT01202188 (SHINE)	Post-hoc analysis of the multicenter, randomized, double-blind, placebo-controlled, phase III trial GLOW1, the multicenter, randomized, double-blind, placebo-controlled with open-label, parallel group phase III trial GLOW2, the blinded, double-dummy, parallel group trial GLOW5 and the multicenter randomized, double-blind, placebo and active controlled, trial SHINE	3.0 (GLOW5); 6.0 (SHINE, GLOW1); 12.0 (GLOW2)	2936	GLOW1: GLY 50 μg QD vs PCB GLOW2; GLY 50 μg QD vs open-label T 18 μg QD vs PCB GLOW5: GLY 50 μg QD vs T 18 μg QD SHINE: IND/GLY 110/50 μg QD vs IND 150 μg QD vs GLY 50 μg QD vs open-label T 18 μg QD vs PCB;	COPD, age ≥40 years, current or past smokers of (≥10 pack- years), post- bronchodilator FEV1 ≥30–<80% predicted, and post-bronchodilator FEV1/ FVC ratio <0.70	63.8	73.3	41.2	NA	54.9	NA	48.0	NA	NA	4 (GLOW1), 5 (GLOW2), 5 (GLOW5), 5 (SHINE)
Anzueto et al 2018 29925383^Citation46	NCT01782326 (FLAME)	Post-hoc analysis of the multicenter, randomized, double-blind, double-dummy, parallel-group trial FLAME	12.0	3362	IND/GLY 110/50 μg QD vs SAL/FP 50/500 μg BID	COPD, age ≥40 years, post-bronchodilator FEV1 ≥25% and<60% predicted, documented history of ≥1 COPD exacerbation in the previous 12 months, mMRC grade≥2.	64.5	76.0	39.6	NA	44.0	NA	47.2	NA	NA	5
Singh et al 2017 28558833^Citation47	NCT01462942 (ACLIFORM); NCT01437397 (AUGMENT)	Post-hoc analysis of pooled data from the multicenter randomized, double-blind, placebo-controlled, active-controlled, parallel group, phase III trials ACLIFORM and AUGMENT	6.0	2680	AB/FOR 400/12 μg BID vs AB/FOR 400/6 μg BID vs AB 400 μg BID vs FOR 12 μg BID vs PCB	Stable moderate to severe COPD (FEV1/FVC ≤70% post bronchodilator, FEV1 of ≥30–<80%predicted post bronchodilator), age ≥40years, current or past smokers.	63.6	60.0	49.2	46.4	53.7	0.4	46.0	NA	NA	5 (ACLIFORM); 4 (AUGMENT)
Anzueto et al 2017 28496316^Citation7	NCT01202188 (SHINE); NCT01709903 (LANTERN); NCT01315249 (ILLUMINATE)	Post-hoc analysis of the pooled data from the multicenter randomized, double-blind, placebo and active controlled, trial SHINE, the multicenter, randomized, double-blind, double-dummy, placebo controlled, parallel-group trial LANTERN and the multicenter, randomized, double-blind, double-dummy, parallel-group, placebo controlled trial ILLUMINATE	6.0	2217	SHINE: IND/GLY 110/50 μg QD vs IND 150 μg QD vs GLY 50 μg QD vs open-label T 18 μg QD vs PCB; LANTERN: 110/50 μg QD vs SAL/FP 50/500 μg BID vs PCB; ILLUMINATE: IND/GLY 110/50 μg QD vs SAL/FP 50/500 μg BID vs PCB	SHINE: Moderate to very severe COPD according to GOLD 2017, age ≥40years, post-bronchodilator FEV1 ≥30% and<80% predicted, post-bronchodilator, FEV1/FVC <70%; LANTERN: age ≥40years, current or past smokers (≥10 pack-years), post-bronchodilator FEV1 ≥30% and<80% predicted, post-bronchodilator, FEV1/FVC <70%; ILLUMINATE: age ≥40years, current or past smokers (≥10 pack-years), post-bronchodilator FEV1 ≥40% and<80% predicted, post-bronchodilator, FEV1/FVC <70%	64.1	79.6	37.1	NA	55.3	NA	NA	NA	NA	5 (SHINE); 5 (LANTERN); 5 (ILLUMINATE)
Maleki-Yazdi et al 2017 27796912^Citation48	NCT01316900 (DB2113360); NCT01316913 (DB2113374); NCT01777334 (ZEP117115)	Post-hoc analysis of pooled data from the multicenter randomized, blinded, double-dummy, parallel-group trials DB2113360, DB2113374 and ZEP117115	6.0	1747	ZEP117115: UMEC/VI 62.5/25 μg QD vs T 18 μg QD; DB2113360: UMEC/VI 62.5/25 μg QD vs T 18 μg QD vs VI 25 μg QD vs, UMEC/VI 125/25 μg QD; DB2113374: UMEC/VI 62.5/25 μg QD vs T 18 μg QD vs UMEC 125 μg QD vs, UMEC/VI 125/25 μg QD	COPD according to ATS 2004, age ≥40years, mMRC grade≥2, FEV1 of ≤70% predicted post-bronchodilator, FEV1/FVC <70%. Maintenance-naïve population: no maintenance therapy for ≥30 days before screening.	63.2	68.1	51.3	45.6	47.0	NA	NA	NA	NA	4 (DB2113360); 4 (DB2113374); 5 (ZEP117115)
Singh et al 2016 27445468^Citation2	NCT01313650 (DB2113373); NCT01777334 (ZEP117115)	Post-hoc analysis of the pooled data from the multicenter randomized, double-blind, parallel-group, phase III trials DB2113373 and ZEP117115	6.0	2437	DB2113373 (StudyA): UMEC/VI 62.5/25 μg QD vs UMEC 62.5 μg QD vs VI 25 μg QD vs PCB; ZEP117115: (Study B) UMEC/VI 62.5/25 μg QD vs T 18 μg QD	COPD according to ATS 2004, age ≥40years, mMRC grade≥2, FEV1 of ≤70% predicted post-bronchodilator, FEV1/FVC <70%.	62.8	69.6	52.2	45.5	47.0	NA	49.1	NA	NA	5 (DB2113373); 5 (ZEP117115)

Abbreviations: AB, aclidinium bromide; AECOPD, acute exacerbation of COPD; ATS, American Thoracic Society; BDP, beclomethasone dipropionate; BID, bis in die, twice daily; BUD, budesonide; CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in the first second; FF, fluticasone furoate; FOR, formoterol fumarate; FP, fluticasone propionate; FVC, forced vital capacity; GLY, glycopyrronium bromide or glycopyrrolate; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long-acting β₂-adrenoceptor agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified medical research council dyspnea scale; NA, not available; O, olodaterol; PCB, placebo; PMID, PubMed IDentifier; QD, quaque die, once daily; SAL, salmeterol; SGRQ, St. George’s Respiratory Questionnaire; T, tiotropium bromide; UMEC, umeclidinium bromide; VI, vilanterol.

Table 2 Different CID Definitions Used in the Studies Included in the Systematic Review and Meta-Regression Analysis

Study, Year, PMID, and Reference	FEV1 Decline and/or	Exacerbations and/or	SGRQ Increase and/or	CAT Increase and/or	Other Items
Han et al 2021 33718490^Citation35	≥100 mL (12 months study follow-up)	A moderate/ severe exacerbation (12 months study follow-up)	Increase ≥4 units in SGRQ (12 months study follow-up)	≥2 units increase in CAT (12 months study follow-up)
Rabe et al 2021 3317529^Citation36	≥100 mL (12 months study follow-up)	A moderate/ severe exacerbation (12 months study follow-up)	Increase ≥4 units in SGRQ (12 months study follow-up)	NA	NA
Kerwin et al 2020 33061349^Citation37	≥100 mL post-bronchodilator FEV1 (3 months study follow-up) ≥100 mL over the first 6 months	A moderate or severe healthcare resource utilization-related exacerbation (3 months study follow-up)	Increase ≥4 units in SGRQ (3 months study follow-up)	NA	NA
Rabe et al 2020 32646424^Citation38	≥100 mL (pre-bronchodilator) during at least two consecutive assessments (5 or 6 months apart)	A moderate/ severe exacerbation (48 months study follow-up)	Increase ≥4 units in SGRQ during at least two consecutive assessments (5 or 6 months apart)	NA	NA
Zheng et al 2020 32164675^Citation39	≥100 mL (6 months study follow-up)	A moderate or severe exacerbation (6 months study follow-up)	Increase ≥4 units in SGRQ (6 months study follow-up)	NA	NA
Chen et al 2020 32021143^Citation40	≥100 mL (6 months study follow-up)	A moderate or severe exacerbation (6 months study follow-up)	Increase ≥4 units in SGRQ (6 months study follow-up)	NA	NA
Bafadhel et al 2020 31924197^Citation41	≥100mL pre-dose (6.5 months study follow-up for SHINE and RISE trials, 13 months for SUN and US3 trials)	A moderate or severe exacerbation after the first dose of study medication (6.5 months study follow-up for SHINE and RISE trials, 13 months for SUN and US3 trials)	Increase ≥4 units in SGRQ (6.5 months study follow-up for SHINE and RISE trials, 13 months for SUN and US3 trials)	NA	NA
Maltais et al 2019 31666084^Citation42	Definition A and B: ≥100 mL Definition C: NA (6 months study follow-up)	Definition A, B and C: moderate or severe exacerbation (6 months study follow-up)	Definition A and C: Increase ≥ 4 units in SGRQ Definition B: NA 6 months study follow-up)	Definition A: NA Definition B and C: ≥2 units increase in CAT (6 months study follow-up)	Definition A and B: NA Definition C: ≥1 unit decrease in TDI (6 months study follow-up)
Singh et al 2019 30880943^Citation43	Classic and TRILOGY definition: ≥ 100 mL (12 months study follow-up) Sustained: if maintained at all subsequent visits	Classic and TRILOGY definition: A moderate/ severe exacerbation or death (12 months study follow-up) Alternative sustained CID definition: if accompanied by a CID in FEV1 and/or SGRQ at all subsequent visits (and/or TDI focal score in the additional TRILOGY analysis), or study discontinuation due to the event, or at least one further exacerbation	Classic and TRILOGY definition: Increase ≥ 4 units in SGRQ (12 months study follow-up) Sustained: if maintained at all subsequent visits	Classic and TRILOGY definition: NA	Classic definition: NA TRILOGY definition: ≥1 unit decrease in TDI focal score Sustained: if maintained at all subsequent visits
Naya et al 2018 30191464^Citation44	≥100 mL (3 months study follow-up)	A moderate/ severe exacerbation (3 months study follow-up)	Increase ≥ 4 units in SGRQ (3 months study follow-up)	NA	NA
Naya et al 2018 30302335^Citation6	SGRQ-containing CID and CAT-containing CID: ≥100 mL (6 months study follow-up)	SGRQ-containing CID and CAT-containing CID: a moderate/ severe exacerbation (6 months study follow-up)	SGRQ-containing CID: increase ≥ 4 units in SGRQ CAT-containing CID: NA (6 months study follow-up)	SGRQ-containing CID: NA CAT-containing CID: ≥2 units increase in CAT (6 months study follow-up)	SGRQ-containing CID and CAT-containing CID: NA
D’Urzo et al 201829795478^Citation45	≥100mL pre-dose (GLOW5: 3 months study follow-up; SHINE and GLOW1: 6 months study follow-up; GLOW2: 12 months study-follow-up)	A moderate to severe exacerbation (GLOW5: 3 months study follow-up; SHINE and GLOW1: 6 months study follow-up; GLOW2: 12 months study-follow-up)	Increase ≥ 4 units in SGRQ (GLOW5: 3 months study follow-up; SHINE and GLOW1: 6 months study follow-up; GLOW2: 12 months study-follow-up)	NA	NA
Anzueto et al 201829925383^Citation46	≥100mL pre-dose (12 months study follow-up)	A moderate to severe exacerbation (12 months study follow-up)	Increase ≥ 4 units in SGRQ (12 months study follow-up	NA	NA
Singh et al 2017 28558833^Citation47	≥100 mL pre-dose (6 months study follow-up)	A moderate/ severe exacerbation (6 months study follow-up)	Increase ≥ 4 units in SGRQ (6 months study follow-up	NA	≥1 unit decrease in TDI (6 months study follow-up)
Anzueto et al 2017 28496316^Citation7	Definition 1: ≥100 mL Definition 2: NA (6.5 months study follow-up) Sustained: if present on two consecutive visits at least 4 weeks apart, or on >50% of all subsequent visits	Definition 1 and 2: an on-treatment moderate-to-severe exacerbation (6.5 months study follow-up)	Definition 1 and 2: increase ≥ 4 units in SGRQ (6.5 months study follow-up) Sustained: if present on two consecutive visits at least 4 weeks apart, or on >50% of all subsequent visits	Definition 1 and 2: NA	Definition 1: NA Definition 2: ≥1 unit decrease in TDI (6.5 months study follow-up) Sustained: if present on two consecutive visits at least 4 weeks apart, or on >50% of all subsequent visits
Maleki-Yazdi et al 2017 27796912^Citation48	≥100 mL (6 months study follow-up) Sustained: ≥100 mL on two consecutive visits, or for ≥50% of all available subsequent visits	A COPD exacerbation (6 months study follow-up) Sustained: if leading to study withdrawal	Increase ≥ 4 units in SGRQ (6 months study follow-up) Sustained: if present on two consecutive visits, or for ≥50% of all available subsequent visits	NA	NA
Singh et al 2016 27445468^Citation2	≥100 mL (6 months study follow-up)	An on-treatment moderate-to-severe exacerbation (6 months study follow-up)	Increase ≥ 4 units in SGRQ (6 months study follow-up)	NA	NA

Abbreviations: CAT, COPD assessment test; CID, clinically important deterioration; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in the first second; PMID, PubMed IDentifier; SGRQ, St. George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Figure 2 Forest plot of meta-analysis concerning the impact of pharmacological treatment on the risk of CID in COPD.

Notes: The subgroup and overall effect estimates resulting from the meta-analysis are reported in bold; the red-dashed line indicates the average relative risk resulting for the overall effect estimate.

Abbreviations: AB, aclidinium bromide; BUD, budesonide; CID, clinically important deterioration; COPD, chronic obstructive pulmonary disease; FF, fluticasone furoate; FOR, formoterol fumarate; FP, fluticasone propionate; GLY, glycopyrronium bromide or glycopyrrolate; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long-acting β₂-adrenoceptor agonist; LABD, long-acting bronchodilators; LAMA, long-acting muscarinic antagonist; O, olodaterol; PCB, placebo; SAL, salmeterol; T, tiotropium bromide; UMEC, umeclidinium bromide; VI, vilanterol.

Figure 3 Graphical representation of the meta-regression analysis for age with respect to the risk of CID.

Note: The size of the circles is proportional to the sample weights.

Abbreviation: CID, clinically important deterioration.

Figure 4 Funnel plot (A) and graphical representations of Egger’s test (B).

Notes: Funnel plot represents a visual approach to check for the existence of publication bias by assessing the symmetry of study distribution, whereas Egger’s test is a regression assay that permits to statistically quantify the extent of Funnel plot asymmetry; dotted lines in the Egger’s test represent 90% prediction bands.

Abbreviation: SND, standard normal deviate.

Figure 5 CID risk increases in older patients with worse lung function.

Notes: The meta-regression analysis suggested that age significantly modulates the risk of CID when associated with lower post-bronchodilator FEV₁.

Abbreviation: CID, clinically important deterioration; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in the first second.

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