Trial Outcomes & Findings for Cardiovascular Events in Chronic Obstructive Pulmonary Disease Patients Initiating Olodaterol or Other Long-acting beta2 Agonists (NCT NCT03405363)

Results Overview

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).

Recruitment status

COMPLETED

Target enrollment

65406 participants

Primary outcome timeframe

Up to 4 years and 11 months

Results posted on

2021-04-30

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Olodaterol 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.	Other Long-acting beta2-agonist (LABAs) 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.
Overall Study STARTED	14239	51167
Overall Study COMPLETED	14239	51167
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Olodaterol n=14239 Participants 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.	Other Long-acting beta2-agonist (LABAs) n=51167 Participants 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 n=65406 Participants Total of all reporting groups
Age, Continuous	72.7 Years STANDARD_DEVIATION 10.0 • n=14239 Participants	72.7 Years STANDARD_DEVIATION 10.0 • n=51167 Participants	72.7 Years STANDARD_DEVIATION 10.0 • n=65406 Participants
Sex: Female, Male Female	7649 Participants n=14239 Participants	27253 Participants n=51167 Participants	34902 Participants n=65406 Participants
Sex: Female, Male Male	6590 Participants n=14239 Participants	23914 Participants n=51167 Participants	30504 Participants n=65406 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.

PRIMARY outcome

Timeframe: Up to 4 years and 11 months

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

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).

Outcome measures

Outcome measures
Measure	Olodaterol n=14239 Participants 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.	Other Long-acting beta2-agonist (LABAs) n=51167 Participants 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.
Occurrence of First Hospitalisation or Hospital Outpatient Clinic Visit for Atrial Fibrillation or Flutter (AF)	246 Events	725 Events

PRIMARY outcome

Timeframe: Up to 4 years and 11 months

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

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).

Outcome measures

Outcome measures
Measure	Olodaterol n=14239 Participants 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.	Other Long-acting beta2-agonist (LABAs) n=51167 Participants 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.
Occurrence of First Hospitalisation or Hospital Outpatient Clinic Visit for Supraventricular Tachycardia (SVT) (Other Than Atrial Fibrillation/Flutter)	19 Events	38 Events

PRIMARY outcome

Timeframe: Up to 4 years and 11 months

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

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).

Outcome measures

Outcome measures
Measure	Olodaterol n=14239 Participants 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.	Other Long-acting beta2-agonist (LABAs) n=51167 Participants 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.
Occurrence of First Hospitalisation for Ventricular Tachycardia (VT), Including Ventricular Fibrillation/Flutter and Cardiac Arrest	29 Events	80 Events

PRIMARY outcome

Timeframe: Up to 4 years and 11 months

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

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).

Outcome measures

Outcome measures
Measure	Olodaterol n=14239 Participants 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.	Other Long-acting beta2-agonist (LABAs) n=51167 Participants 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.
Occurrence of First Hospitalisation for Acute Myocardial Infarction (AMI)	56 Events	137 Events

PRIMARY outcome

Timeframe: Up to 4 years and 11 months.

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

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).

Outcome measures

Outcome measures
Measure	Olodaterol n=14239 Participants 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.	Other Long-acting beta2-agonist (LABAs) n=51167 Participants 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.
Occurrence of First Hospitalisation for Serious Acute Coronary Heart Disease (SACHD), Including Angina and Other Acute Ischaemic Heart Disease Events	41 Events	147 Events

SECONDARY outcome

Timeframe: Up to 4 years and 11 months.

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Olodaterol n=14239 Participants 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.	Other Long-acting beta2-agonist (LABAs) n=51167 Participants 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.	859 Events	1872 Events

Adverse Events

Olodaterol

Serious events: 0 serious events

Other events: 0 other events

Deaths: 859 deaths

Other Long-acting beta2-agonist (LABAs)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 1872 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
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