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Background: Recent observational studies have reported possible arrhythmogenic effects with long-acting beta-agonists (LABA), while the long-acting anticholinergic tiotropium has been associated with cardiovascular and cerebrovascular events. Finally, pneumonia was the object of a recent signal in trials of LABAs submitted for marketing approval.
Aim: To assess the potential cardio-pulmonary risk arising from the concurrent use of two long-acting bronchodilators as well as from monotherapy use of each of the long-acting bronchodilators.
Methods: A series of population-based cohort studies, using both cohort and nested case-control analyses will be conducted using data from the United Kingdom's Clinical Practice Research Datalink (CPRD). The base cohort will consist of new users of long-acting bronchodilators from Jan 2002 until Aug 2012, age >= 55 with chronic obstructive pulmonary disease (COPD) and at least two years of baseline medical history information. The high-dimensional propensity score technique will be used to match new users of each long-acting bronchodilator and new users of two bronchodilators with comparable subjects from the base cohort, with one-year follow-up for outcomes of acute myocardial infarction, stroke, heart failure, arrhythmia and community acquired pneumonia. Data will be analysed using time-dependent Cox proportional hazard regression models and conditional logistic regression models.
Purpose:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| LABA + tiotropium | |||
| LABA mono | |||
| neither tiotropium nor LABA | |||
| tiotropium + LABA | |||
| tiotropium mono |
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| Measure | Description | Time Frame |
|---|---|---|
| Myocardial Infarction | The acute myocardial infarction (MI) rate per 1000 patients per year after matching on high-dimensional propensity score and inhaled corticosteroid (ICS) use in the year prior to cohort entry. No. = Number | Up to 12 months |
| Stroke | The stroke rate per 1000 patients per year after matching on high-dimensional propensity score and inhaled corticosteroid (ICS) use in the year prior to cohort entry. | Up to 12 months |
| Heart Failure | The heart failure (HF) rate per 1000 patients per year after matching on high-dimensional propensity score and inhaled corticosteroid (ICS) use in the year prior to cohort entry. | Up to 12 months |
| Cardiac Arrhythmia | The cardiac arrhythmia (CA) rate per 1000 patients per year after matching on high-dimensional propensity score and inhaled corticosteroid (ICS) use in the year prior to cohort entry. | Up to 12 months |
| Community Acquired Pneumonia | The community acquired pneumonia rate per 1000 patients per year after matching on high-dimensional propensity score and inhaled corticosteroid (ICS) use in the year prior to cohort entry. Pt. = Patient | Up to 12 months |
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Inclusion criteria:
Exclusion criteria:
- Use of LABA or tiotropium in the two years prior to cohort entry
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Users of tiotropium or long-acting beta agonists
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| Name | Affiliation | Role |
|---|---|---|
| Boehringer Ingelheim | Boehringer Ingelheim | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boehringer Ingelheim Investigational Site | Montreal | Quebec | Canada |
Patients receiving combination therapy were those who either added tiotropium to LABA, or added LABA to tiotropium.
In the Participant Flow & Baseline Characteristics modules, no participants were represented in both the "Tiotropium" & the "LABA" Arms/Groups.
The base cohort included 115,397 new users of tiotropium or a LABA (+/- ICS) between 01Jan2002 & 31Aug2013.These patients included 26,442 new users of tiotropium & 88,955 new users of LABA.Patients initiating treatment with both bronchodilators on the same date were excluded.
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| ID | Title | Description |
|---|---|---|
| FG000 | Tiotropium | Participants who were new users of tiotropium. |
| FG001 | LABA | Participants who were new users of a long-acting beta2 agonist (LABA) with or without inhaled corticosteroid (ICS). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Patients who were new users of tiotropium or a long-acting beta agonist (LABA) with or without ICS. Estimates based on overall patients before propensity score matching (base cohort).
New use was defined as a first use of either bronchodilator without use of either drug of interest during the previous two years
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| ID | Title | Description |
|---|---|---|
| BG000 | Tiotropium | Participants who were new users of tiotropium. |
| BG001 | LABA | Participants who were new users of a long-acting beta2 agonist (LABA) with or without inhaled corticosteroid (ICS). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Myocardial Infarction | The acute myocardial infarction (MI) rate per 1000 patients per year after matching on high-dimensional propensity score and inhaled corticosteroid (ICS) use in the year prior to cohort entry. No. = Number | The subset of patients from the base cohort who were either on monotherapy (who stayed on monotherapy) or combination therapy (who added tiotropium to LABA or added LABA to tiotropium) and were matched via propensity score. | Posted | Number | No. of incident MI/1000patients/ year | Up to 12 months |
|
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Given the study design, serious and other (non-serious) adverse events were not collected and therefore adverse event data is not presented
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tiotropium | Participants who were new users of tiotropium. |
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Study measures may be subject to misclassification. Diagnoses codes based on read codes and not laboratory or clinical measures. Residual confounding is possible as the analysis is dependent on only recorded information in patients' clinical records.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boehringer Ingelheim Call Center | Boehringer Ingelheim | 1-800-243-0127 | clintriage.rdg@boehringer-ingelheim.com |
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| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| ID | Term |
|---|---|
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D002908 | Chronic Disease |
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| BG002 | Total | Total of all reporting groups |
| Years |
|
| Gender | Count of Participants | Participants |
|
Participants who added another long-acting bronchodilator to the previous long-acting bronchodilator (Tiotropium plus LABA+/-ICS) - combination therapy
|
|
|
| Primary | Stroke | The stroke rate per 1000 patients per year after matching on high-dimensional propensity score and inhaled corticosteroid (ICS) use in the year prior to cohort entry. | The subset of patients from the base cohort who were either on monotherapy (who stayed on monotherapy) or combination therapy (who added tiotropium to LABA or added LABA to tiotropium) and were matched via propensity score. | Posted | Number | No. of incident stroke/1000patients/year | Up to 12 months |
|
|
|
|
| Primary | Heart Failure | The heart failure (HF) rate per 1000 patients per year after matching on high-dimensional propensity score and inhaled corticosteroid (ICS) use in the year prior to cohort entry. | The subset of patients from the base cohort who were either on monotherapy (who stayed on monotherapy) or combination therapy (who added tiotropium to LABA or added LABA to tiotropium) and were matched via propensity score. | Posted | Number | No. of incident HF/1000patients/year | Up to 12 months |
|
|
|
|
| Primary | Cardiac Arrhythmia | The cardiac arrhythmia (CA) rate per 1000 patients per year after matching on high-dimensional propensity score and inhaled corticosteroid (ICS) use in the year prior to cohort entry. | The subset of patients from the base cohort who were either on monotherapy (who stayed on monotherapy) or combination therapy (who added tiotropium to LABA or added LABA to tiotropium), who can be linked to the Hospital Episode Statistics database, and were matched via propensity score. | Posted | Number | No. of incident CA/1000patients /year | Up to 12 months |
|
|
|
|
| Primary | Community Acquired Pneumonia | The community acquired pneumonia rate per 1000 patients per year after matching on high-dimensional propensity score and inhaled corticosteroid (ICS) use in the year prior to cohort entry. Pt. = Patient | The subset of patients from the base cohort who were either on monotherapy (who stayed on monotherapy) or combination therapy (who added tiotropium to LABA or added LABA to tiotropium), who can be linked to the Hospital Episode Statistics database, and were matched via propensity score. | Posted | Number | No.of incident Pneumonia/1000 pt./year | Up to 12 months |
|
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|
|
| 0 |
| 0 |
| 0 |
| 0 |
| EG001 | LABA | Participants who were new users of a long-acting beta2 agonist (LABA) with or without inhaled corticosteroid (ICS). | 0 | 0 | 0 | 0 |
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.
| D020969 |
| Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |