Cardiovascular Events in Chronic Obstructive Pulmonary Disease Patients Initiating Olodaterol or Other Long-acting beta2 Agonists

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03405363
• Collaborator: (none)
• Enrollment: 65,406
• Location: 1
• Actual Duration (Months): 24.1
• Patients Per Site Per Month: 2716

Study Details

Study Description

Brief Summary

Examine the risk of cardiovascular events (cardiac arrhythmia or myocardial ischemia) or all-cause mortality in Chronic Obstructive Pulmonary Disease (COPD) patients who are new users of Olodaterol or other LABAs available for the treatment of COPD.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive

Detailed Description

Purpose:

Time Perspective:

Study Design

• Study Type: Observational
• Actual Enrollment: 65406 participants
• Observational Model: Cohort
• Time Perspective: Other
• Official Title: Cohort Study of Cardiovascular Events in Patients With Chronic Obstructive Pulmonary Disease Initiating Olodaterol or Other Long-acting beta2-agonists
• Actual Study Start Date: Jan 31, 2018
• Actual Primary Completion Date: Feb 3, 2020
• Actual Study Completion Date: Feb 3, 2020

Arms and Interventions

Arm	Intervention/Treatment
new users of Olodaterol COPD patients using Olodaterol for the first time
new users of other LABAs COPD patients using other long-acting beta2 agonists for the first time

Outcome Measures

Primary Outcome Measures

1. Occurrence of First Hospitalisation or Hospital Outpatient Clinic Visit for Atrial Fibrillation or Flutter (AF) [Up to 4 years and 11 months]

   Cases of AF were ascertained by at least one (=first occurrence) International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) code for primary hospital inpatient discharge diagnosis or as a diagnosis code in a hospital outpatient specialist visit in the Danish National Patient Registry while being new users of olodaterol or of any Long-Acting Beta2-Agonist (LABA) other than olodaterol. The exposure window considered only the first episode of continuous use, defined as the time comprising consecutive dispensing's separated by up to 14 days. Termination dates of the follow up: date of outcome of interest, disenrollment from the database, 14 days after estimated discontinuation of the last dispensing for index LABA, the date the patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019).

2. Occurrence of First Hospitalisation or Hospital Outpatient Clinic Visit for Supraventricular Tachycardia (SVT) (Other Than Atrial Fibrillation/Flutter) [Up to 4 years and 11 months]

   Cases of SVT were ascertained by at least one (=first occurrence) ICD-10 code for primary hospital inpatient discharge diagnosis or as a diagnosis code in a hospital outpatient specialist visit in the Danish National Patient Registry while being new users of olodaterol or of any Long-Acting Beta2-Agonist (LABA) other than olodaterol. The exposure window considered only the first episode of continuous use, defined as the time comprising consecutive dispensing's separated by up to 14 days. Termination dates of the follow up: date of outcome of interest, disenrollment from the database, 14 days after estimated discontinuation of the last dispensing for index LABA, the date the patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019).

3. Occurrence of First Hospitalisation for Ventricular Tachycardia (VT), Including Ventricular Fibrillation/Flutter and Cardiac Arrest [Up to 4 years and 11 months]

   Cases of VT were ascertained by at least one (=first occurrence) ICD-10 code for primary hospital inpatient discharge diagnosis in the Danish National Patient Registry while being exposed to olodaterol and other LABA monotherapy or in free or fixed-dose combination with long-acting muscarinic antagonist (LAMA). The exposure window considered only the first episode of continuous use, defined as the time comprising consecutive dispensing's separated by up to 14 days. Termination dates of the follow up: date of outcome of interest, disenrollment from the database, 14 days after estimated discontinuation of the last dispensing for index LABA, the date the patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019).

4. Occurrence of First Hospitalisation for Acute Myocardial Infarction (AMI) [Up to 4 years and 11 months]

   Cases of AMI were ascertained by at least one (=first occurrence) ICD-10 code for primary hospital inpatient discharge diagnosis in the Danish National Patient Registry while being new users of olodaterol or of any Long-Acting Beta2-Agonist (LABA) other than olodaterol. The exposure window considered only the first episode of continuous use, defined as the time comprising consecutive dispensing's separated by up to 14 days. Termination dates of the follow up: date of outcome of interest, disenrollment from the database, 14 days after estimated discontinuation of the last dispensing for index LABA, the date the patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019).

5. Occurrence of First Hospitalisation for Serious Acute Coronary Heart Disease (SACHD), Including Angina and Other Acute Ischaemic Heart Disease Events [Up to 4 years and 11 months.]

   Cases of SACHD were ascertained by at least one (=first occurrence) ICD-10 code for primary hospital inpatient discharge diagnosis in the Danish National Patient Registry while being new users of olodaterol or of any Long-Acting Beta2-Agonist (LABA) other than olodaterol. The exposure window considered only the first episode of continuous use, defined as the time comprising consecutive dispensing's separated by up to 14 days. Termination dates of the follow up: date of outcome of interest, disenrollment from the database, 14 days after estimated discontinuation of the last dispensing for index LABA, the date the patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019).

Secondary Outcome Measures

1. All-cause Mortality. [Up to 4 years and 11 months.]

   Death ascertained from Danish Civil Registration System (fact and date of death, but not cause of death) while being new users of olodaterol or any Long-Acting Beta2-Agonist (LABA) other than olodaterol. Exposure window: first episode of continuous use (= time comprising consecutive dispensing's separated by up to 14 days). Termination dates of the follow up: date of outcome of interest, disenrollment from database, 14 days after estimated discontinuation of last dispensing for index LABA, date patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019). To assess possible impact of imbalanced baseline characteristics, all-cause mortality was further assessed in two post-hoc analyses with restricted populations that would be more similar at baseline, post-hoc population 1 and post-hoc population 2.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• COPD diagnosis

• aged 40 years or older (to minimise the likelihood of including individuals who have asthma only)

• New user of olodaterol or a new user of indacaterol, salmeterol, or formoterol (not in fixed-dose combination with an inhaled corticosteroid) and have no dispensing of any LABA in the 6 months before the index date

• at least 1 year of enrolment in the electronic database before their first LABA dispensing (defined as the index LABA)

• Complete data on sex

Exclusion criteria:

none

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aarhus Universitets hospital Skejby	Aarhus		Denmark

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 28, 2016

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03405363
• Other Study ID Numbers: 1222.54
• First Posted: Jan 23, 2018
• Last Update Posted: Apr 30, 2021
• Last Verified: Apr 1, 2021

• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Recruitment Details

This cohort study, used data from the Danish National Patient Registry (diagnoses), Danish Prescription Database (dispensings), and Danish Register of Causes of Death (cause of death information) to examine the risk of cardiovascular events in patients with chronic obstructive pulmonary disease (COPD) exposed to olodaterol compared to other long-acting beta2-agonists (LABAs) between 01 March 2014 and 31 January 2019.

Pre-assignment Detail

Only subjects that met all inclusion and none of the exclusion criteria were included. The matched cohort study design and propensity score methodology were used to establish two comparable treatment cohorts, the Olodaterol cohort and the other LABA cohort.

Arm/Group Title	Olodaterol	Other Long-acting beta2-agonist (LABAs)
Arm/Group Description	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry initiating olodaterol (either alone or in free- or fixed-dose combination with a Long-Acting Muscarinic Antagonist (LAMA)), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry (March 2014 to January 2019) initiating LABA (alone or in a free- or fixed-dose combination with a LAMA), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.
Period Title: Overall Study
STARTED	14239	51167
COMPLETED	14239	51167
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Olodaterol	Other Long-acting beta2-agonist (LABAs)	Total
Arm/Group Description	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry initiating olodaterol (either alone or in free- or fixed-dose combination with a Long-Acting Muscarinic Antagonist (LAMA)), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry (March 2014 to January 2019) initiating LABA (alone or in a free- or fixed-dose combination with a LAMA), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.	Total of all reporting groups
Overall Participants	14239	51167	65406
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	72.7 (10.0)	72.7 (10.0)	72.7 (10.0)
Sex: Female, Male (Count of Participants)
Female	7649 53.7%	27253 53.3%	34902 53.4%
Male	6590 46.3%	23914 46.7%	30504 46.6%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Occurrence of First Hospitalisation or Hospital Outpatient Clinic Visit for Atrial Fibrillation or Flutter (AF)
Description	Cases of AF were ascertained by at least one (=first occurrence) International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) code for primary hospital inpatient discharge diagnosis or as a diagnosis code in a hospital outpatient specialist visit in the Danish National Patient Registry while being new users of olodaterol or of any Long-Acting Beta2-Agonist (LABA) other than olodaterol. The exposure window considered only the first episode of continuous use, defined as the time comprising consecutive dispensing's separated by up to 14 days. Termination dates of the follow up: date of outcome of interest, disenrollment from the database, 14 days after estimated discontinuation of the last dispensing for index LABA, the date the patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019).
Time Frame	Up to 4 years and 11 months

Outcome Measure Data

Analysis Population Description

Propensity score-trimmed population of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry

Arm/Group Title	Olodaterol	Other Long-acting beta2-agonist (LABAs)
Arm/Group Description	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry initiating olodaterol (either alone or in free- or fixed-dose combination with a Long-Acting Muscarinic Antagonist (LAMA)), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry (March 2014 to January 2019) initiating LABA (alone or in a free- or fixed-dose combination with a LAMA), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.
Measure Participants	14239	51167
Number [Events]	246	725

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Other Long-acting beta2-agonist (LABAs)
	Comments
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Olodaterol compared to 'other LABA' as reference

2. Primary Outcome

Title	Occurrence of First Hospitalisation or Hospital Outpatient Clinic Visit for Supraventricular Tachycardia (SVT) (Other Than Atrial Fibrillation/Flutter)
Description	Cases of SVT were ascertained by at least one (=first occurrence) ICD-10 code for primary hospital inpatient discharge diagnosis or as a diagnosis code in a hospital outpatient specialist visit in the Danish National Patient Registry while being new users of olodaterol or of any Long-Acting Beta2-Agonist (LABA) other than olodaterol. The exposure window considered only the first episode of continuous use, defined as the time comprising consecutive dispensing's separated by up to 14 days. Termination dates of the follow up: date of outcome of interest, disenrollment from the database, 14 days after estimated discontinuation of the last dispensing for index LABA, the date the patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019).
Time Frame	Up to 4 years and 11 months

Outcome Measure Data

Analysis Population Description

Propensity score-trimmed population of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry.

Arm/Group Title	Olodaterol	Other Long-acting beta2-agonist (LABAs)
Arm/Group Description	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry initiating olodaterol (either alone or in free- or fixed-dose combination with a Long-Acting Muscarinic Antagonist (LAMA)), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry (March 2014 to January 2019) initiating LABA (alone or in a free- or fixed-dose combination with a LAMA), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.
Measure Participants	14239	51167
Number [Events]	19	38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Other Long-acting beta2-agonist (LABAs)
	Comments	No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	1.83
	Confidence Interval	(2-Sided) 95%; 0.90 to 3.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	Olodaterol compared to 'other LABA' as reference

3. Primary Outcome

Title	Occurrence of First Hospitalisation for Ventricular Tachycardia (VT), Including Ventricular Fibrillation/Flutter and Cardiac Arrest
Description	Cases of VT were ascertained by at least one (=first occurrence) ICD-10 code for primary hospital inpatient discharge diagnosis in the Danish National Patient Registry while being exposed to olodaterol and other LABA monotherapy or in free or fixed-dose combination with long-acting muscarinic antagonist (LAMA). The exposure window considered only the first episode of continuous use, defined as the time comprising consecutive dispensing's separated by up to 14 days. Termination dates of the follow up: date of outcome of interest, disenrollment from the database, 14 days after estimated discontinuation of the last dispensing for index LABA, the date the patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019).
Time Frame	Up to 4 years and 11 months

Outcome Measure Data

Analysis Population Description

Propensity score-trimmed population of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry.

Arm/Group Title	Olodaterol	Other Long-acting beta2-agonist (LABAs)
Arm/Group Description	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry initiating olodaterol (either alone or in free- or fixed-dose combination with a Long-Acting Muscarinic Antagonist (LAMA)), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry (March 2014 to January 2019) initiating LABA (alone or in a free- or fixed-dose combination with a LAMA), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.
Measure Participants	14239	51167
Number [Events]	29	80

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Other Long-acting beta2-agonist (LABAs)
	Comments	No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95%; 0.71 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Olodaterol compared to 'other LABA' as reference

4. Primary Outcome

Title	Occurrence of First Hospitalisation for Acute Myocardial Infarction (AMI)
Description	Cases of AMI were ascertained by at least one (=first occurrence) ICD-10 code for primary hospital inpatient discharge diagnosis in the Danish National Patient Registry while being new users of olodaterol or of any Long-Acting Beta2-Agonist (LABA) other than olodaterol. The exposure window considered only the first episode of continuous use, defined as the time comprising consecutive dispensing's separated by up to 14 days. Termination dates of the follow up: date of outcome of interest, disenrollment from the database, 14 days after estimated discontinuation of the last dispensing for index LABA, the date the patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019).
Time Frame	Up to 4 years and 11 months

Outcome Measure Data

Analysis Population Description

Propensity score-trimmed population of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry.

Arm/Group Title	Olodaterol	Other Long-acting beta2-agonist (LABAs)
Arm/Group Description	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry initiating olodaterol (either alone or in free- or fixed-dose combination with a Long-Acting Muscarinic Antagonist (LAMA)), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry (March 2014 to January 2019) initiating LABA (alone or in a free- or fixed-dose combination with a LAMA), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.
Measure Participants	14239	51167
Number [Events]	56	137

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Other Long-acting beta2-agonist (LABAs)
	Comments	No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Olodaterol compared to 'other LABA' as reference

5. Primary Outcome

Title	Occurrence of First Hospitalisation for Serious Acute Coronary Heart Disease (SACHD), Including Angina and Other Acute Ischaemic Heart Disease Events
Description	Cases of SACHD were ascertained by at least one (=first occurrence) ICD-10 code for primary hospital inpatient discharge diagnosis in the Danish National Patient Registry while being new users of olodaterol or of any Long-Acting Beta2-Agonist (LABA) other than olodaterol. The exposure window considered only the first episode of continuous use, defined as the time comprising consecutive dispensing's separated by up to 14 days. Termination dates of the follow up: date of outcome of interest, disenrollment from the database, 14 days after estimated discontinuation of the last dispensing for index LABA, the date the patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019).
Time Frame	Up to 4 years and 11 months.

Outcome Measure Data

Analysis Population Description

Propensity score-trimmed population of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry.

Arm/Group Title	Olodaterol	Other Long-acting beta2-agonist (LABAs)
Arm/Group Description	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry initiating olodaterol (either alone or in free- or fixed-dose combination with a Long-Acting Muscarinic Antagonist (LAMA)), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry (March 2014 to January 2019) initiating LABA (alone or in a free- or fixed-dose combination with a LAMA), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.
Measure Participants	14239	51167
Number [Events]	41	147

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Other Long-acting beta2-agonist (LABAs)
	Comments	No formal hypotheses were tested.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Olodaterol compared to 'other LABA' as reference

6. Secondary Outcome

Title	All-cause Mortality.
Description	Death ascertained from Danish Civil Registration System (fact and date of death, but not cause of death) while being new users of olodaterol or any Long-Acting Beta2-Agonist (LABA) other than olodaterol. Exposure window: first episode of continuous use (= time comprising consecutive dispensing's separated by up to 14 days). Termination dates of the follow up: date of outcome of interest, disenrollment from database, 14 days after estimated discontinuation of last dispensing for index LABA, date patient switched to another LABA, dispensing of a second LABA, death, end of study period (= 31 January 2019). To assess possible impact of imbalanced baseline characteristics, all-cause mortality was further assessed in two post-hoc analyses with restricted populations that would be more similar at baseline, post-hoc population 1 and post-hoc population 2.
Time Frame	Up to 4 years and 11 months.

Outcome Measure Data

Analysis Population Description

Propensity score-trimmed population of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry. Post-hoc population 1 was based on propensity score-trimmed population restricted to users of fixed-dose combination of LABA/LAMA who were LABA-treatment naïve (= no LABA dispensing in the 180 days before cohort entry). Post-hoc population 2 was post-hoc population 1 further restricted to users without hospitalizations for COPD in the last 90 days.

Arm/Group Title	Olodaterol	Other Long-acting beta2-agonist (LABAs)
Arm/Group Description	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry initiating olodaterol (either alone or in free- or fixed-dose combination with a Long-Acting Muscarinic Antagonist (LAMA)), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry (March 2014 to January 2019) initiating LABA (alone or in a free- or fixed-dose combination with a LAMA), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.
Measure Participants	14239	51167
Number [Events]	859	1872

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Other Long-acting beta2-agonist (LABAs)
	Comments	Analysis was based on Propensity score-trimmed population of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry.
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	1.63
	Confidence Interval	(2-Sided) 95%; 1.44 to 1.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	Olodaterol compared to 'other LABA' as reference

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Other Long-acting beta2-agonist (LABAs)
	Comments	Analysis based on post-hoc population 1. Adjustments: propensity score decile, previous use of: LAMA, oxygen, inhaled glucocorticoid, respiratory medications, fixed-dose combinations of Short-Acting Beta2- Agonist and Short-Acting Muscarinic Antagonist and systemic antibacterials. COPD severity, number of: all-cause hospitalisations 365 and 180 days, COPD exacerbations 180 and 90 days, COPD hospitalisations 180 and 90 days, and COPD exacerbations 90 days before index date.
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Incidence Rate Ratio
	Estimated Value	1.48
	Confidence Interval	(2-Sided) 95%; 1.23 to 1.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Olodaterol compared to 'other LABA' as reference

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Other Long-acting beta2-agonist (LABAs)
	Comments	Analysis based on post-hoc population 2. Adjustments: propensity score decile, previous use of: LAMA, oxygen, inhaled glucocorticoid, respiratory medications. COPD severity, number of all-cause hospitalisations 180 days, COPD exacerbations 180 days before cohort entry.
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Incidende Rate Ratio
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.97 to 1.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	Olodaterol compared to 'other LABA' as reference

Adverse Events

Time Frame	Up to 4 years and 11 months
Adverse Event Reporting Description	This is a non-interventional study using electronic health care records, with data retrieved from Danish National Patient Registry, Danish National Prescription Registry and Danish Register of Causes of Death. No adverse events were collected on an individual case level. All-cause mortality (ACM) is an outcome of this study and thus additionally reported below. Please note, adjusted incidence rate ratios of ACM are displayed as statistical analyses 1, 2, 3 of the secondary outcome measure 6.
Arm/Group Title	Olodaterol		Other Long-acting beta2-agonist (LABAs)
Arm/Group Description	Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry initiating olodaterol (either alone or in free- or fixed-dose combination with a Long-Acting Muscarinic Antagonist (LAMA)), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.		Cohort of patients with Obstructive Pulmonary Disease (COPD) derived from the Danish Patient Registry (March 2014 to January 2019) initiating LABA (alone or in a free- or fixed-dose combination with a LAMA), with first dispensing as index date occurred from 01 March 2014 (launch of olodaterol in Denmark) to 31 January 2019 (last date with data available for the final data cut). Participants were matched 1:4 ('olodaterol' : 'other LABAs') by age, sex, and calendar year.
All Cause Mortality
	Olodaterol		Other Long-acting beta2-agonist (LABAs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	859/14239 (6%)		1872/51167 (3.7%)
Serious Adverse Events
	Olodaterol		Other Long-acting beta2-agonist (LABAs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Olodaterol		Other Long-acting beta2-agonist (LABAs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.