Table 2.
Observational studies evaluating risk of cardiovascular events with LABA and LAMA use in COPD patients.
| Reference | Study design | Population | Exclusion for CVD | New-user design (yes/no) | Exposures | Cases or outcome definitions | Results |
|---|---|---|---|---|---|---|---|
| AU et al. (2000) [12] | Case-control design | Cases: postmenopausal women and hypertensive male aged 30–79 years Controls: patients aged 30–79 years |
Excluded prior MI | Yes, but no exclusion of exposure prior to cohort entry. | Any MDI β-agonist prescriptions in the two years before the index/ event date, and new use, defined as β-agonists prescription only filled for one time in the 90 days before the index date. | Incident nonfatal or fatal MI | MDIβ-agonists vs non-use: aOR (95%CI) New use: 1.67 (1.07–2.60)a |
| Grosso et al. (2009) [58] | Selfcontrolled case-series design | Patients receiving any tiotropium prescription and diagnosed with ≥ 1 stroke event | Excluded carotid endarterectomy > 6 weeks prior to events | No. | Exposure periods in which patients using tiotropium or fluticasone plus salmeterol vs. other unexposed observation periods. | First-ever diagnosis of ischaemic, haemorrhagic or unspecified stroke within the study time window | IRR (95%CI)
|
| Wilchesky et al. (2012) - Part 1 [13] | Nested case-control design | Saskatchewan cohort, COPD patients aged ≥55 years with at least one bronchodilator use | No exclusion of CVD | Yes, but no exclusion of exposure of interest preceding cohort entry. | One of the exposures was LABA use. Current use: a LABA prescription in 60 days preceding the index/ event date. Current new use: current use but no prescription in 61–365 days before the index/ event date. |
Arrhythmic death or hospital admission with a primary discharge diagnosis of arrhythmia | LABA vs. non-use: aOR (95%CI)
|
| Wilchesky et al. (2012) - Part2 [14] | Nested case-control design | Quebec Cohort, COPD patients aged ≥67 years with at least one bronchodilator use | No exclusion of CVD | Yes, but no exclusion of LABA use preceding cohort entry | One of the exposures was LABA use. Current use: a LABA prescription in 60 days preceding the index/ event date. Current new use: current use but no prescription in 61–365 days before the index/ event date. |
Arrhythmic death or hospital admission with a primary discharge diagnosis of arrhythmia | LABA vs. non-use: aOR (95%CI)
|
| Gershon et al. (2013) [15] | Nested case–control design | COPD patients aged ≥66 years and receiving ≥1 COPD medication | No exclusion of CVD | Yes, but no exclusion of LABA or LAMA prior to cohort entry | New LABA and LAMA use defined as any LABA and LAMA prescription within 90 days of the index/event date and not receiving any same medication in the previous year. | A hospital or an ED visit for cardiovascular events, including acute coronary syndrome (including MI), HF, ischemic stroke, or cardiac arrhythmia | aOR (95%CI) New use vs. non-use: New LABA vs. new LAMA: 1.15 (0.95–1.38) |
| Lee et al. (2015) [54] | Nested case-control design | Patients dispensing inhaled respiratory drugs for 30 days or longer | Excluded acute major CVD events including MI, stroke and tachyarrhythmia during the year prior to the cohort entry | Yes, excluded inhaled respiratory drugs during the year before cohort entry | LABA, LAMA and ICS + LABA, defined based on the inhaler prescriptions for 30 days or longer during the 90-day before the index/ event date. | First-time diagnosis of tachyarrhythmia | aOR (95%CI) |
| Tsai et al. (2015) [56] | Cohort design | COPD patients aged ≥18 years | Excluded stroke, HF, VA, MI, or angina before the index date | No. | LAMA + LABA and LABA + ICS combinations vs. LABA only. | Incident cardiocerebrovascular events including hospital for stroke, HF, VA, MI, or angina. | Combinations vs. LABA: aHR (95%CI) |
| Dong et al. (2016) [51] | Cohort design | COPD patients aged ≥ 40 years initiating inhaled long-acting bronchodilators | No exclusion of CVD | Yes. Excluded LABA or LAMA within 1 year before cohort entry date | LAMA or LABA only, and LABA + LAMA. | First hospitalization for a composite cardiovascular event, comprising MI, HF, or cerebrovascular diseases (including ICH or ischemic stroke) | aHR (95%CI) Intention to treat:
|
| Suissa et al. (2017) [53] | HDPS-matched cohort design | COPD patients aged ≥55 years with LABA or tiotropium use | No exclusion of CVD | Yes. Excluded any prescription of LABA or tiotropium during the previous 2 years before cohort entry | LABA added to tiotropium or vice versa vs. monotherapy. | MI, HF, stroke based on general practitioner’s diagnostic code and arrhythmia from hospitalization diagnoses | LABA + LAMA vs. LABA or LAMA: aHR (95%CI)
|
| Samp et al. (2017) [59] | PS-matched cohort design | COPD patients aged ≥ 40 years initiating a LABA + LAMA or LABA + ICS | No exclusion of CVD | Yes. Excluded patients with a claim for a LABA + LAMA or LABA + ICS during 30 days prior to the index date | LABA + LAMA vs. LABA + ICS. | One hospitalization for a cardiovascular event including CAD, HF or cardiac dysrhythmia or a cerebrovascular event comprised of stroke or TIA | LABA + LAMA vs. LABA + ICS: HR (95%CI)
|
| Suissa et al. (2017) [52] | HDPS-matched cohort design | COPD patients aged ≥ 55 years using LABA or tiotropium | No exclusion of CVD | Yes. Excluded prevalent users of LABA or tiotropium at cohort entry | New users of LABA or tiotropium. | MI, HF, stroke based on general practitioner’s diagnostic code and arrhythmia from hospitalization diagnoses | Tiotropium vs. LABA: aHR (95%CI)
|
| Liou et al. (2018) [55] | DRS-matched nested case –control design | COPD patients aged ≥40 years and receiving LABA and ICS combination | Excluded congenital heart disease and CVD at cohort entry | Yes. Excluded any tiotropium prescription filled in the year before cohort entry | Added tiotropium use in the year before the index/event date, further classified by different recency of therapy, new and prevalent use. | First inpatient or ED visit with a primary diagnosis of CAD, HF, ischemic stroke, or cardiac arrhythmia | Tiotropium vs. non-use: aOR (95%CI)
|
| Wang et al. (2018) [16] | DRS-matched nested case –control design | COPD patients aged ≥40 years and receiving ≥1 COPD medication | No exclusion of CVD | Yes. Excluded any LABA or LAMA therapy in 1 year preceding cohort entry | LABA and LAMA use in the year before the index/event date, further classified as different recency of therapy, new use and prevalent use. | Inpatient or ED visit with a primary diagnosis of CAD, HF, ischemic stroke, or cardiac arrhythmia | Current use: aOR (95%CI)
|
Abbreviations: LABA, long-acting β2 agonists; LAMA, long-acting muscarinic antagonists; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction; MDI, metered dose inhaler; aOR, adjusted odds ratio; 95%CI, 95% confidence interval; IRR, incidence rate ratio; CVD, cardiovascular disease; ED, emergency department; HF, heart failure; ICS, inhaled corticosteroid; VA, ventricular arrhythmia; HR, hazard ratio; aHR, adjusted hazard ratio; ICH, intracerebral hemorrhage; PS, propensity score; HDPS, high dimensional propensity score; DRS, disease risk score; TIA, transient ischemic attack; CAD, coronary artery disease.
Statistically significant.