Randomized controlled trials and real-world observational studies in evaluating cardiovascular safety of inhaled bronchodilator therapy in COPD

Figures & data

Table 1 RCTs reporting on the CV and cerebrovascular safety of LAMA/LABA combination therapy

Reference	N trial participants	Treatment arms	Safety outcomes assessed	CV and cerebrovascular outcomes
UMEC/VI
Celli et al (2014)^Citation5	1,493 randomized; 1,489 in ITT	UMEC/VI 125/25 µg; UMEC 125 µg; VI 25 µg; placebo	AEs, vital signs, 12-lead ECG, 24-h Holter ECG, clinical chemistry, and hematology assessments	No clinically meaningful changes in vital signs, ECG assessments (including 12-lead and Holter recordings), and clinical laboratory tests were observed for UMEC/VI, UMEC, or VI compared with placebo
Naccarelli et al (2014)^Citation24	6,156 in the MACE analysis; 5,295 in the CV AESIs analysis	Pooled analysis of 8 RCTs of: UMEC/VI 125/25 µg; UMEC/VI 62.5/25 µg; UMEC 62.5 µg; UMEC 125 µg; VI 25 µg; or active-comparator (TIO)	Broad MACE analysis included MedDRA preferred terms for “MI”, and “Other ischemic heart disease”. Narrow MACE specified “acute MI” and “MI only”; both analyses also included adjudicated CV death and nonfatal stroke CV AESIs: acquired long QT interval, cardiac arrhythmias, cardiac failure, cardiac ischemia, hypertension, sudden death, and stroke	No clinically relevant increase in CV events was observed with UMEC/VI, UMEC, or VI compared with placebo
Maltais et al (2014)^Citation23	Study 1: 308 randomized; 307 patients in ITT population Study 2: 349 randomized; 348 in ITT population	UMEC/VI 125/25 µg; UMEC/VI 62.5/25 µg; VI 25 µg; UMEC 62.5 µg; UMEC 125 µg; placebo	AEs, exacerbations, vital signs, clinical chemistry parameters, hematology parameters, and 12-lead ECGs	Proportion of patients with abnormal, clinically significant ECG assessments was similar across all treatments
Siler et al (2015)^Citation25	Study 1: 619 randomized and in ITT population Study 2: 620 randomized; 619 in ITT population	UMEC 62.5 mg; UMEC 125 mg; placebo (added to open-label fluticasone furoate (FF)/VI)	AEs, vital signs (pulse rate and systolic and diastolic BP), exacerbations, and AESIs (CV events, pneumonia, and lower respiratory tract infections)	Incidence of CV AESIs was low and similar across all treatment groups
Hu et al (2015)^Citation22	20 randomized	UMEC/VI 62.5/25 µg; UMEC/VI 125/25 µg; UMEC 62.5 µg; UMEC 125 µg; VI 25 µg	AEs, SAEs, vital signs (systolic and diastolic BP and HR), 12-lead ECG, maximum 0–4 h QTcF, maximum 0–4 h HR, 0–4 h weighted mean QTcF and 0–4 h weighted mean HR, clinical chemistry, hematology, and urinalysis	No clinically important changes in vital signs, HR, or ECG parameters were observed for each treatment group
Decramer et al (2014)^Citation7	Study 1: 846 randomized; 843 in ITT population Study 2: 872 randomized; 869 in ITT population	UMEC/VI 125/25 µg; UMEC/VI 62.5/25 µg; TIO 18 µg; VI 25 µg (Study 1); UMEC 125 µg (Study 2)	AEs, SAEs, vital signs, ECG, and laboratory data	No notable difference in BP, HR, or QT interval observed between treatment groups in either study, and no treatment-related changes in ECG parameters
Maleki-Yazdi et al (2014)^Citation10	905 randomized and in ITT population	UMEC/VI 62.5/25 µg; TIO 18 µg	AEs, SAEs, and AESIs (CV events, pneumonia, and lower respiratory tract infections)	Incidence of CV AESIs was equivalent between UMEC/VI 62.5/25 µg and TIO 18 µg
Donohue et al (2014)^Citation8	563 randomized; 562 in ITT population	UMEC/VI 125/25 µg; UMEC 125 µg; placebo	AEs, vital signs, clinical chemistry, hematology, 12-lead ECG, 24-h Holter ECG, and AESIs (CV effects, effects on glucose and potassium, tremor, urinary retention, ocular effects, gallbladder disorders, intestinal obstruction, and anticholinergic effects)	Lower overall incidence of CV AEs with UMEC/VI than UMEC or placebo Proportion of patients with one or more abnormal, clinically significant 12-lead ECG interpretation or with one or more abnormal, clinically significant Holter ECG interpretation similar across all treatment groups Incidence of atrial arrhythmias with UMEC/VI similar to placebo, but some arrhythmias had a ≥2% greater incidence with UMEC compared with placebo No clinically relevant differences in QTc interval, PR interval, or HR observed between treatments
Donohue et al (2016)^Citation26	Study 1: 207 randomized and in ITT population Study 2: 182 randomized and in ITT population	UMEC/VI 62.5/25 µg; UMEC 62.5 µg; VI 25 µg	AEs, vital signs, and COPD exacerbations; Study 2 only: 12-lead ECGs, and clinical laboratory tests (hematology and clinical chemistry)	No clinically significant changes in QT interval (corrected for HR by Bazett’s and Fridericia’s formulae), PR interval, HR, or changes in these parameters from baseline observed Six patients were withdrawn due to ECG abnormalities (UMEC/VI: 4; UMEC: 1; VI: 1)
TIO/olodaterol
Singh et al (2015)^Citation27	Study 1: 814 randomized; 812 treated; Study 2: 809 randomized and treated	TIO/olodaterol 5/5 µg; TIO/olodaterol 2.5/5 µg; TIO 5 µg; placebo	AEs, SAEs, vital signs, and 12-lead ECG	Incidences of AEs in the “cardiac disorders” Systems Organ Class were similar across treatments
ZuWallack et al (2014)^Citation28	Study 1: 1,134 randomized; 1,132 treated; Study 2: 1,137 randomized; 1,135 treated	TIO/Olodaterol 18/5 µg; TIO 18 µg + placebo	AEs, SAEs, vital signs, blood chemistry, and ECG	No changes in laboratory parameters, vital signs, or ECG were indicative of a safety signal
Buhl et al (2015)^Citation17	Study 1: 2,624 randomized and treated; Study 2: 2,539 randomized; 2,538 treated	TIO/olodaterol 2.5/5 µg; TIO/olodaterol 5/5 µg; TIO 2.5 µg; TIO 5 µg; olodaterol 5 µg	AEs, SAEs, vital signs, laboratory parameters, and MACE (in subset of patients with cardiac history)	The incidences of MACE were similar with TIO/olodaterol and individual components
Aclidinium/formoterol
Singh et al (2014)^Citation30	1,729 in safety analysis set	Aclidinium/formoterol 400/12 µg; aclidinium/formoterol 400/6 µg; aclidinium 400 µg; formoterol 12 µg; placebo	AEs, laboratory tests, BP, 12-lead ECG, 24-h 12-lead Holter recordings, and MACE (a composite of total CV death, nonfatal MI, and nonfatal stroke)	The incidence of MACE was low and comparable across all groups There were no clinically significant differences between treatment groups in clinical laboratory tests, vital signs, and ECGs (including 24-h or 12-lead Holter recordings)
D’Urzo et al (2014)^Citation29	1,692 randomized; 1,668 in ITT population	Aclidinium/formoterol 400/12 µg; aclidinium/formoterol 400/6 µg; aclidinium 400 µg; formoterol 12 µg; placebo	AEs, clinical laboratory tests, vital signs, ECGs, 24-h 12-lead Holter monitoring, and MACE (composite of CV deaths, nonfatal MIs, and nonfatal strokes)	Number of MACEs were infrequent and occurred at similar incidences across all treatment groups Holter monitoring did not show any findings of an ECG effect for patients in any group, and no differences were observed between treatments
Indacaterol/glycopyrronium
Mahler et al (2014)^Citation31	247 randomized	Indacaterol/glycopyrronium 110/50 µg; TIO 18 µg; placebo	AEs, SAEs, physical examinations, laboratory assessments, ECGs, and vital signs	The incidence of SAEs was similar across groups and serious CV and cerebrovascular AEs were infrequent One death (left ventricular failure leading to cardiac arrest) occurred in the indacaterol/glycopyrronium group
Van de Maele et al (2010)^Citation21	257 randomized	Indacaterol/glycopyrronium 600/100 µg; indacaterol/glycopyrronium 300/100 µg; indacaterol/glycopyrronium 150/100 µg; Indacaterol 300 µg; Placebo	Primary endpoint: change from baseline in 24-h mean HR versus placebo on day 14	No clinically significant differences in the 24-h mean HR between the three doses of indacaterol/glycopyrronium and placebo or indacaterol No clinically relevant differences in QTc interval (Fridericia’s) between groups
Bateman et al (2013)^Citation6	2,144 randomized	Indacaterol/glycopyrronium 110/50 µg; indacaterol 150 µg; glycopyrronium 50 µg; TIO 18 µg; placebo	AEs, SAEs, ECGs, hematology, clinical chemistry, urinalysis, physical condition, and vital signs (pulse and BP) 24-h Holter monitoring in a subset of patients	No serious CV and cerebrovascular events in the indacaterol/glycopyrronium group and few reported and adjudicated in the other treatment groups Atrial fibrillation/flutter events (ie, reported as AEs, SAEs, or ECG findings) were uncommon in all groups No clinically relevant differences in QTc interval (Fridericia’s formula) between treatment groups
Wedzicha et al (2014)^Citation32	11,404 pooled from 14 RCTs	Indacaterol/glycopyrronium 110/50 µg; glycopyrronium 50 µg; indacaterol 150 µg; TIO 18 µg; placebo	All-cause mortality, CV, cerebrovascular events, and MACE (nonfatal MI, unstable angina, nonfatal stroke, heart failure, and coronary revascularization)	No significant increase in overall risk for serious CV and cerebrovascular events, MACEs, or atrial flutter/fibrillation for indacaterol/glycopyrronium versus placebo No significant increase in risk for indacaterol/glycopyrronium versus placebo for any of the CV safety endpoints for all subgroup analyses based on COPD severity, baseline ICS use, CV risk factors, sex, age, or BMI Risk was comparable to those for TIO versus placebo
Mahler et al (2015)^Citation33	2,038 pooled from 2 RCTs	Indacaterol/glycopyrrolate (27.5/15.6 µg twice daily); indacaterol 27.5 µg twice daily; glycopyrrolate 15.6 µg twice daily; placebo	AEs, SAEs, CV, cerebrovascular AEs, SAEs, and MACE	Incidence of CV and cerebrovascular AEs and MACE was comparable across treatments Patients with at least one CV and cerebrovascular SAE were comparable across treatments

Abbreviations: AE, adverse event; AESI, adverse event of special interest; BMI, body mass index; BP, blood pressure; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; ECG, electrocardiogram; HR, heart rate; ICS, inhaled corticosteroid; ITT, intent-to-treat; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; MACE, major adverse cardiovascular event; MedDRA, Medical Dictionary for Regulatory Activities; MI, myocardial infarction; RCT, randomized controlled trial; SAE, serious adverse event; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

Table 2 Primary and secondary study safety outcomes in the 201038 Post-authorization Safety Study of UMEC/VI combination therapy

Primary study safety outcomes	Secondary study safety outcomes
Time to first event of each of MI, stroke, and heart failure (new or acute worsening)	Time to first composite safety endpoint (MI, stroke, heart failure, or sudden cardiac death)
Incidence ratea of each of MI, stroke, and heart failure (new or acute worsening)	Incidence ratea of composite safety endpoint (MI, stroke, heart failure, or sudden cardiac death)
Total number of events of each of MI, stroke, and heart failure (new or acute worsening)	Incidence ratea and total number events of hemorrhagic stroke, ischemic stroke, undefined stroke, and hospitalization for heart failure
	Incidence ratea of serious pneumonia/LRTI
	Total number of events and event rate of all pneumonia/LRTI AEs
	Mortality rate (all-cause, CV-related, and non-CV-related)
	CV AEs of special interestb, drug-related AEs, all SAEsc, and all deaths

Notes:

a Per person year;

b including transient ischemic attacks, angina, cardiac arrhythmias, acquired long-QT interval, cardiac ischemia and hypertension;

c according to MedDRA SOC and PT; All treatment comparisons of primary and secondary safety outcomes will be analyzed using hazard ratios for time to first event.

Abbreviations: AE, adverse event; CV, cardiovascular; LRTI, lower respiratory tract infection; MedDRA, medical dictionary for regulatory activities; MI, myocardial infarction; PT, preferred term; SAE, serious adverse event; SOC, system organ class; UMEC, umeclidinium; VI, vilanterol.

Figure 1 Study design for the new 201038 Post-authorization Safety Study of UMEC/VI combination therapy.

Note: *The follow-up period will be defined as the period between the prescription index date until the earliest of: date when the planned number of events has been reached, 14 days following date of discontinuation of initiated COPD medication, withdrawal from the study, conclusion of study follow-up or death.
Abbreviations: COPD, chronic obstructive pulmonary disease; HCP, health care practitioner; TIO, tiotropium; VI, vilanterol; UMEC, umeclidinium.

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