Adding a Second Bronchodilator in COPD: A Meta-Analysis on the Risk of Specific Cardiovascular Serious Adverse Events of Tiotropium/Olodaterol Fixed-Dose Combination

Figures & data

Figure 1. PRISMA flow diagram for the identification of the full text articles included in the meta-analysis concerning the impact of T/O 5/5 μg FDC vs. monocomponents on the risk of arrhythmia, heart failure, myocardial infarction, and stroke in COPD patients enrolled in RCTs. COPD: chronic obstructive pulmonary disease; CV: cardiovascular; FDC: fixed-dose combination; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCTs: randomized controlled trials; SAEs: serious adverse events; T/O: tiotropium/olodaterol.

Table 1. Patient demographics, baseline and study characteristics.

Study and year	ClinicalTrials.gov Identifier and study name	Study characteristics	Duration of treatment (weeks)	Number of analyzed patients	Drugs and active comparators (doses)	Inhaler device (brand)	Administration regimen	Patients characteristics	Age (years)	Male (%)	Current smokers (%)	Smoking history (pack-years)	Post bronchodilator FEV1 (% predicted)	Jadad score
Calverley et al., 2018 [31]	NCT02296138; DYNAGITO	Phase 3, multicentre, randomized, double-blind, active-controlled, parallel-group	52	7,880	Tiotropium/olodaterol 5/5 μg FDC vs. tiotropium 5 μg	Soft Mist Inhaler (Respimat^®)	Once-daily	FEV1 <60% predicted and a history of at least one moderate or severe exacerbation in the last year	66.4	72	37	44.8	44.6	4
Troosters et al., 2018 [32]	NCT02085161; PHYSACTO	Phase 3, randomized, partially double-blind, placebo-controlled, parallel-group	12	228	Tiotropium/olodaterol 5/5 μg FDC vs. tiotropium 5 μg	Soft Mist Inhaler (Respimat^®)	Once-daily	FEV1 ≥30% and <80% predicted	64.8	68.3	NA	>10	NA	4
O' Donnell et al., 2017 [33]	NCT01533922, NCT01533935; MORACTO 1 and 2	Phase 3, replicate, randomized, double-blind, placebo-controlled, incomplete-crossover	6	450	Tiotropium/olodaterol 5/5 μg FDC vs. tiotropium 5 μg and vs. olodaterol 5 μg	Soft Mist Inhaler (Respimat^®)	Once-daily	FEV1 ≥30% and <80% predicted	61.7	71.2	39.1	45.8	52.0	3
Ichinose et al., 2017 [34]	NCT01536262	Phase 3, multicentre, randomized, double-blind, active-controlled, parallel-group	52	82	Tiotropium/olodaterol 5/5 μg FDC vs. olodaterol 5 μg	Soft Mist Inhaler (Respimat^®)	Once-daily	FEV1 <80% predicted	69.8	95.2	28.1	60.3	59.4	4
Beeh et al., 2015 [35]	NCT01559116	Phase 3, multicentre randomized, double-blind, placebo-controlled, incomplete-crossover	6	139	Tiotropium/olodaterol 5/5 μg FDC vs. tiotropium 5 μg and vs. olodaterol 5 μg	Soft Mist Inhaler (Respimat^®)	Once-daily	FEV1 <80% predicted^#	61.1	58.9	62.6	NA	54.0	3
Buhl et al., 2015 [36]	NCT01431287, NCT01431274	Phase 3, multicentre, multinational, replicate, randomized, double-blind, parallel-group, active-controlled, five-arm	52	3,100	Tiotropium/olodaterol 5/5 μg FDC vs. tiotropium 5 μg and vs. olodaterol 5 μg	Soft Mist Inhaler (Respimat^®)	Once-daily	FEV1 <80% predicted	64.0	72.9	37.0	>10	50.0	3
Singh et al., 2015 [37]	NCT02006732, NCT01964352; OTEMTO 1 and 2	Phase 3, multinational, replicate, randomized, double-blind, placebo-controlled, parallel group	12	811	Tiotropium/olodaterol 5/5 μg FDC vs. tiotropium 5 μg	Soft Mist Inhaler (Respimat^®)	Once-daily	FEV1 ≥30% and <80% predicted	64.8	61.2	47.7	>10	55.1	3

# In German sites only.

BDI: Baseline Dyspnea Index; FEV₁: forced expiratory volume in 1 s; FDC: fixed-dose combination; FRC: functional residual capacity; FVC: forced vital capacity; NA: not available.

Figure 2. Forest plot of pairwise meta-analysis of the impact of T/O 5/5 μg FDC vs. monocomponents on the risk of arrhythmia (A), heart failure (B), myocardial infarction (C), and stroke (D) in COPD patients. Each forest plot reports also the subset analysis with regard to the effect of the class of monocomponents included in the FDC (T/O 5/5 μg FDC vs. T 5 μg or vs. O 5 μg). COPD: chronic obstructive pulmonary disease; FDC: fixed-dose combination; LABA: long-acting β₂ adrenoceptor agonist; LAMA: long-acting muscarinic antagonist; O: olodaterol; T: tiotropium.

Table 2. Pooled analysis of the frequency of specific CV SAEs (arrhythmia, heart failure, myocardial infarction, and stroke) in COPD patients treated with T/O 5/5 μg FDC and their monocomponents. Data were extracted from RCTs in the repository database ClinicalTrials.gov that reported at least one specific CV SAEs in the investigated arms. The frequencies were ranked in agreement with EMA guideline.

	T/O 5/5 μg FDC				T 5 μg				O 5 μg
Specific CV SAEs:	Patients	Cases	Frequency % (95%CI)	Rank	Patients	Cases	Frequency % (95%CI)	Rank	Patients	Cases	Frequency % (95%CI)	Rank
arrhythmia	5,061	29	0.55 (0.37 – 0.79)	uncommon	5,062	29	0.157 (0.39 – 0.81)	uncommon	1,038	4	0.39 (0.12 – 0.93)	uncommon
heart failure	5,533	55	0.99 (0.75 – 1.28)	uncommon/common	4,972	51	1.03 (0.77 – 1.34)	uncommon/common	1,079	4	0.37 (0.12 – 0.89)	uncommon
myocardial infarction	5,064	30	0.59 (0.40 – 0.84)	uncommon	5,066	27	0.53 (0.36 – 0.76)	uncommon	1,038	4	0.39 (0.12 – 0.93)	uncommon
stroke	5,033	9	0.18 (0.09 – 0.33)	uncommon	5,019	9	0.18 (0.09 – 0.33)	uncommon	1,054	3	0.28 (0.07 – 0.77)	uncommon

95%CI: 95% confidence interval; COPD: chronic obstructive pulmonary disease; CV: cardiovascular; EMA: European Medicine Agency; FDC: fixed-dose combination; O: olodaterol; SAEs: serious adverse events; RCTs: randomized controlled trials; T: tiotropium.

Figure 3. Publication bias assessment via funnel plots (left panels) and Egger’s test (right panels) for the impact of T/O 5/5 μg FDC vs. monocomponents on the risk of arrhythmia (A and B), heart failure (C and D), myocardial infarction (E and F), and stroke (G and H) in COPD patients. COPD: chronic obstructive pulmonary disease; FDC: fixed-dose combination; O: olodaterol; T: tiotropium.

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