The impact of dual bronchodilation on cardiovascular serious adverse events and mortality in COPD: a quantitative synthesis

Figures & data

Figure 1 PRISMA flow diagram for the identification of studies included in the meta-analysis concerning the impact of LABA/LAMA FDCs on cardiovascular SAEs in COPD patients.

Abbreviations: COPD, chronic obstructive pulmonary disease; FDCs, fixed-dose combinations; LABAs, long-acting β₂-agonists; LAMAs, long-acting muscarinic antagonists; PK, pharmacokinetic; RCT, randomized controlled trial; SAEs, serious adverse events.

Table 1 Patient demographics, baseline and study characteristics

Study and year	ClinicalTrials.gov identifier	Study characteristics	Duration of study (weeks)	Number of analyzed patients	Drugs (doses)	Inhaler device (brand)	Administration regimen	Patient characteristics	Age (years)	Male (%)	Current smokers (%)	Smoking history (pack-years)	Post-bronchodilator FEV1 (% predicted)	Jadad score
D’Urzo et al (2017)^Citation36	NCT1572792	Randomized, double-blind, parallel-group, placebo- and active-controlled	28	714	Aclidinium/formoterol 400/12 µg	Dry powder inhaler (Genuair^®/Pressair^®)	Twice daily	Moderate-to-severe COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≥30% and <80% predicted)	63.2	51.1	54.9	53.3	53.3	5
Donohue et al (2016)^Citation37	NCT1437540	Randomized, double-blind, parallel-group, active-controlled	52	590	Aclidinium/formoterol 400/12 µg	Dry powder inhaler (Genuair/Pressair)	Twice daily	Moderate-to-severe COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≥30% and <80% predicted)	64.3	55.1	45.4	51.8	51.2	4
Singh et al (2014)^Citation38	NCT1462942	Multicenter, randomized, double-blind, parallel-group, active- and placebo-controlled	24	1,348	Aclidinium/formoterol 400/12 µg	Dry powder inhaler (Genuair/Pressair)	Twice daily	Moderate-to-severe COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≥30% and <80% predicted)	63.2	67.6	47.3	>10	54.3	4
D’Urzo et al (2014)^Citation39	NCT1437397	Multicentre, randomized, double-blind, placebo-controlled	24	1,389	Aclidinium/formoterol 400/12 µg	Dry powder inhaler (Genuair/Pressair)	Twice daily	Moderate-to-severe stable COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≥30% and <80% predicted)	64.1	53.3	51.7	52.5	53.7	3
Mahler et al (2015)^Citation40	NCT1727141, NCT1712516	Identical, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled	12	2,040	Glycopyrronium/indacaterol 15.6/27.5 µg	Dry powder inhaler (Neohaler^®)	Twice daily	Stable COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≥30% and <80% predicted)	63.5	64.8	52.2	>10	54.6	5
Watz et al (2016)^Citation41	NCT1996319	Multicenter, randomized, double-blind, placebo-controlled, crossover	3	193	Glycopyrronium/indacaterol 50/110 µg	NA	Once daily	Moderate-to-severe stable COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 40%–80% predicted)	62.8	65.5	56.7	47.5	61.6	4
Buhl et al (2015)^Citation44	NCT1120717	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, dummy	52	338	Glycopyrronium/indacaterol 50/110 µg	Dry powder inhaler (NA)	Once daily	Moderate-to-severe COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≥30% and <80% predicted)	62.7	76.9	49.2	41.1	53.3	5
Bateman et al (2013)^Citation42	NCT1202188	Multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled	26	1,179	Glycopyrronium/indacaterol 50/110 µg	Dry powder inhaler (Breezhaler^®)	Once daily	Moderate-to-severe stable COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≥30% and <80% predicted)	64.0	77.2	40.0	>10	55.2	4
Wedzicha et al (2013)^Citation43	NCT1120691	Multicenter, randomized, double-blind, parallel-group	64	1,469	Glycopyrronium/indacaterol 50/110 µg	Dry powder inhaler (Breezhaler)	Once daily	Severe-to-very severe COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 <50% predicted)	63.3	75.0	36.6	>10	37.2	5
O’Donnell et al (2017)^Citation45	NCT1533922, NCT1533935	Replicate, randomized, double-blind, placebo-controlled, incomplete-crossover	6	450	Tiotropium/olodaterol 5/5 µg	Soft mist inhaler (Respimat^®)	Once daily	COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≥30% and <80% predicted)	61.7	71.2	39.1	45.8	52.0	3
Ichinose et al (2017)^Citation46	NCT1536262	Multicenter, randomized, double-blind, parallel-group	52	82	Tiotropium/olodaterol 5/5 µg	Soft mist inhaler (Respimat)	Once daily	Moderate-to-very severe COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 <80% predicted)	69.8	95.2	28.1	60.3	59.4	4
Troosters et al (2016)^Citation47	NCT2085161	Randomized, partially double-blind, placebo-controlled, parallel-group	12	227	Tiotropium/olodaterol 5/5 µg	Soft mist inhaler (Respimat)	Once daily	COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≥30% and <80% predicted)	64.8	68.3	NA	>10	NA	4
Beeh et al (2015)^Citation48	NCT1559116	Multicenter randomized, double-blind, placebo-controlled, incomplete-crossover	6	139	Tiotropium/olodaterol 5/5 µg	Soft mist inhaler (Respimat)	Once daily	COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 <80% predicted)#	61.1	58.9	62.6	NA	54.0	3
Buhl et al (2015)^Citation49	NCT1431274, NCT1431287	Multicenter, multinational, replicate, randomized, double-blind, parallel-group, active-controlled, five-arm	52	3,100	Tiotropium/olodaterol 5/5 µg	Soft mist inhaler (Respimat)	Once daily	Moderate-to-very severe COPD (post-bronchodilator FEV1/FVC <0.7; and FEV1 <80% predicted)	64.0	72.9	37.0	>10	50.0	3
Singh et al (2015)^Citation80	NCT1964352, NCT2006732	Multinational, replicate, randomized, double-blind, placebo-controlled, parallel group	12	1,217	Tiotropium/olodaterol 5/5 µg	Soft mist inhaler (Respimat)	Once daily	Moderate-to-severe COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≥30% and <80% predicted)	64.8	61.2	47.7	>10	55.1	3
Donohue et al (2013)^Citation51	NCT1313650	Multicenter, randomized, double-blind, parallel-group, placebo-controlled	24	1,532	Umeclidinium/vilanterol 62.5/25 µg	Dry powder inhaler (NA)	Once daily	COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≤70% predicted)	63.3	70.7	48.2	46.0	47.6	4
Decramer et al (2014)^Citation52	NCT1316900	Multicenter, randomized, double-blind, parallel-group, double-dummy	24	421	Umeclidinium/vilanterol 62.5/25 µg	Dry powder inhaler (Ellipta^®)	Once daily	COPD (categories B or D)	63.7	67.4	44.3	45.4	47.3	5
Siler et al (2016)^Citation53	NCT2152605	Multicenter, randomized, double-blind, placebo-controlled, parallel-group	12	496	Umeclidinium/vilanterol 62.5/25 µg	Dry powder inhaler (Ellipta)	Once daily	COPD (pre- and post-albuterol [salbutamol] FEV1/FVC <0.7; post-albuterol FEV1 ≤70% predicted)	63.4	59	53.5	38.6	47.5	4
Donohue et al (2016)^Citation6	NCT1716520	Multicenter, randomized, double-blind, three-way, complete block cross-over	2	173	Umeclidinium/vilanterol 62.5/25 µg	Dry powder inhaler (Ellipta)	Once daily	Moderate-to-severe COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 ≤70% predicted)	63.2	70	55	41.3	47.8	3
Zheng et al (2015)^Citation54	NCT1636713	Multicenter, randomized, double-blind, placebo-controlled, parallel-group	24	387	Umeclidinium/vilanterol 62.5/25 µg	Dry powder inhaler (NA)	Once daily	COPD (postalbuterol FEV1/FVC <0.7; postalbuterol FEV1 ≤70% predicted; dyspnea score ≥2)	64.2	93	31.5	37.4	NA	4
Maltais et al (2014)^Citation55	NCT1323660, NCT1328444	Multicenter, randomized, placebo-controlled, parallel-group	12	832	Umeclidinium/vilanterol 62.5/25 µg	Dry powder inhaler (Ellipta)	Once daily	Moderate-to-severe stable COPD (post-bronchodilator FEV1/FVC <0.7; FEV1 >35% and <70% predicted)	62.0	56.4	62.0	48.1	51.3	4
Martinez et al (2017)^Citation56	NCT1854645, NCT1854658	Multicenter, randomized, double-blind, placebo-controlled, parallel-group	24	3,259	Glycopyrronium°/formoterol 14.4/9.6 µg	Pressurised metered dose inhaler (Co-Suspension™ Delivery Technology)	Twice daily	Moderate-to-very severe COPD (post-bronchodilator FEV1/FVC <0.7; <80% predicted and ≥750 mL if FEV1 <30% of predicted normal value)	62.9	55.4	53.8	51.2	51.5	4
Hanania et al (2017)^Citation57	NCT1970878	Multicenter, randomized, double-blind, parallel-group, active-controlled	28	2,816	Glycopyrronium°/formoterol 14.4/9.6 µg	Pressurised metered dose inhaler (Co-Suspension Delivery Technology)	Twice daily	Moderate-to-very severe COPD (post-bronchodilator FEV1/FVC <0.7; <80% predicted and ≥750 mL if FEV1 <30% of predicted normal value)	62.8	55.3	54.0	51.0	43.1	4

Notes:

# In German sites only, FEV₁ ≥30%. °Equivalent to glycopyrrolate 18 µg.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; NA, not available.

Figure 2 Forest plot of pair-wise meta-analysis of the impact of the LABA/LAMA FDCs on cardiovascular SAEs in COPD patients.

Note: Overall analysis performed by comparing LABA/LAMA FDCs versus LABAs or LAMAs (A), and subset analysis considering each specific FDC versus monocomponents (B).
Abbreviations: A, aclidinium; COPD, chronic obstructive pulmonary disease; F, formoterol; FDCs, fixed-dose combinations; G, glycopyrronium; I, indacaterol; LABAs, long-acting β₂-agonists; LAMAs, long-acting muscarinic antagonists; O, olodaterol; SAEs, serious adverse events; T, tiotropium; U, umeclidinium; V, vilanterol.

Table 2 Pooled analysis of cardiovascular SAEs extracted from the ClinicalTrials.gov repository database and grouped by frequency in agreement with the EMA guideline⁸¹

Cardiovascular SAEs	LABA/LAMA FDCs	LABAs	LAMAs	Placebo	Cardiovascular SAEs	LABA/LAMA FDCs	LABAs	LAMAs	Placebo
Acute coronary syndrome	+	+	+	ND	Extrasystoles	+	ND	ND	ND
Acute myocardial infarction	++	++	++	++	Femoral artery occlusion	+	ND	ND	ND
Angina pectoris	++	++	++	++	Hypertension	+	++	++	++
Angina unstable	+	+	+	++	Hypertensive crisis	ND	+	+	ND
Aortic aneurysm	+	++	+	ND	Hypertensive emergency	+	ND	ND	ND
Aortic aneurysm rupture	+	ND	ND	ND	Hypotension	+	++	ND	+
Aortic dissection	ND	ND	+	ND	Iliac artery stenosis	+	ND	ND	ND
Aortic stenosis	ND	+	+	+	Intermittent claudication	ND	+	+	ND
Arrhythmia	ND	ND	ND	+	Ischemic cardiomyopathy	+	ND	+	+
Arterial disorder	ND	+	ND	ND	Left ventricular dysfunction	+	ND	ND	+
Arterial occlusive disease	+	+	ND	ND	Leriche syndrome	ND	+	ND	ND
Arterial stenosis	ND	ND	+	ND	Malignant hypertension	+	ND	ND	ND
Arteriosclerosis	+	ND	ND	ND	Mitral valve stenosis	ND	+	ND	ND
Arteriosclerosis coronary artery	+	+	+	+	Myocardial infarction	++	+	++	++
Atrial fibrillation	++	++	++	++	Myocardial ischemia	++	ND	+	++
Atrial flutter	+	ND	++	ND	Palpitations	ND	ND	+	ND
Atrial tachycardia	+	ND	ND	ND	Pericardial effusion	ND	ND	+	ND
Atrioventricular block	ND	+	ND	ND	Pericarditis	ND	ND	+	ND
Atrioventricular block complete	ND	ND	+	+	Peripheral arterial occlusive disease	+	+	+	ND
Atrioventricular block second degree	ND	+	+	ND	Peripheral artery aneurysm	ND	+	+	ND
Bradycardia	+	ND	++	+	Peripheral artery stenosis	+	ND	ND	ND
Bundle branch block left	ND	+	ND	ND	Peripheral artery thrombosis	ND	+	ND	ND
Cardiac arrest	++	++	++	++	Peripheral ischemia	+	+	ND	+
Cardiac disorder	+	ND	ND	ND	Peripheral vascular disorder	++	++	ND	ND
Cardiac failure	+	++	++	++	Phlebitis deep	+	ND	ND	ND
Cardiac failure acute	+	+	+	ND	Right ventricular failure	ND	ND	+	+
Cardiac failure chronic	+	ND	ND	ND	Shock	ND	+	ND	ND
Cardiac failure congestive	++	+	++	ND	Shock hemorrhagic	+	ND	ND	ND
Cardio-respiratory arrest	++	+	++	ND	Sick sinus syndrome	ND	ND	+	+
Cardiogenic shock	+	ND	ND	ND	Sinus tachycardia	+	ND	ND	ND
Cardiomyopathy	ND	ND	+	+	Supraventricular extrasystoles	ND	+	ND	ND
Cardiopulmonary failure	+	ND	+	ND	Supraventricular tachycardia	+	+	+	+
Circulatory collapse	ND	ND	+	ND	Tachycardia	ND	ND	+	ND
Cor pulmonale	ND	ND	+	ND	Thrombophlebitis	ND	+	ND	ND
Cor pulmonale chronic	+	ND	ND	ND	Thrombophlebitis superficial	+	ND	ND	ND
Coronary artery disease	++	++	++	++	Thrombosis	+	ND	ND	ND
Coronary artery occlusion	+	ND	+	ND	Torsade de pointes	ND	+	ND	ND
Coronary artery stenosis	+	ND	ND	ND	Ventricular extrasystoles	ND	ND	ND	+
Death	++	++	++	++	Ventricular fibrillation	ND	+	ND	ND
Deep vein thrombosis	++	+	+	+	Ventricular tachycardia	+	+	ND	ND
Essential hypertension	+	ND	+	ND

Notes: ++: uncommon (≥1/1,000 to <1/100); +: rare (≥1/10,000 to <1/1,000).

Abbreviations: EMA, European Medicine Agency; FDCs, fixed-dose combinations; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; ND, not detectable (frequency not known); SAEs, serious adverse events.

Table 3 Safety profile of LABA/LAMA FDCs according to SUCRA analysis

Treatment	SUCRA value (%)
A/F 400/12	86.00
T/O 5/5	75.67
Placebo	49.67
U/V 62.5/25	47.33
G/F 14.4/9.6	39.00
G/I 15.6/27.5	37.00
G/I 50/110	15.00

Abbreviations: A, aclidinium; F, formoterol; FDCs, fixed-dose combinations; G, glycopyrronium; I, indacaterol; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; O, olodaterol; SUCRA, surface under the cumulative ranking curve; T, tiotropium; U, umeclidinium; V, vilanterol.

Figure 3 Ranking plot of the network on the cardiovascular safety profile of LABA/LAMA FDCs versus placebo in COPD patients.

Note: Treatments have been plotted on the X-axis according to SUCRA (score of 1 being the safest) and on the Y-axis according to the rank of being the best treatment (score of 1 being the safest).
Abbreviations: A, aclidinium; COPD, chronic obstructive pulmonary disease; F, formoterol; FDC, fixed-dose combination; G, glycopyrronium; I, indacaterol; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonists; O, olodaterol; PCB, placebo; SUCRA, surface under the cumulative ranking curve; T, tiotropium; U, umeclidinium; V, vilanterol.

Figure 4 Publication bias assessment via funnel plot (A) and Egger’s test (B) for the impact of LABA/LAMA FDCs on cardiovascular SAEs in COPD patients, versus respective monocomponents.

Note: *P<0.1.
Abbreviations: A, aclidinium; COPD, chronic obstructive pulmonary disease; F, formoterol; FDCs, fixed-dose combinations; G, glycopyrronium; I, indacaterol; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonists; O, olodaterol; OR, odds ratio; SAEs, serious adverse events; SND, standard normal deviate; T, tiotropium; U, umeclidinium; V, vilanterol.

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