Combination Long-Acting Beta-Agonists and Inhaled Corticosteroids Compared With Long-Acting Beta-Agonists Alone in Older Adults With Chronic Obstructive Pulmonary Disease

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Gershon AS, et al. "Combination long-acting β-agonists and inhaled corticosteroids compared with long-acting β-agonists alone in older adults with chronic obstructive pulmonary disease". JAMA. 2014. 312(11):1114-1121.
PubMed

Clinical Question

In patients with Chronic Obstructive Pulmonary Disorder (COPD), is the combination of long-acting beta agonists and inhaled corticosteroids compared to long-acting beta agonists alone more beneficial for long-term use?

Bottom Line

Among older adults with COPD that were not receiving a long acting anticholinergic, the use of long-acting beta agonists (LABA) with inhaled corticosteroids (ICS) was associated with lower risk of composite outcome of death of COPD hospitalization compared to LABA alone.

Major Points

In a retrospective cohort study of patients 66 years and older with COPD not receiving a long-acting anticholinergic medication, LABA and ICS combination therapy was associated with a significantly lower risk of the composite outcome of death or COPD hospitalizations compared with newly prescribed LABAs alone.

Guidelines

According to the Global Initiative for Obstructive Lung Disease (GOLD) guidelines for COPD, the use of ICS is recommended for patients in stage 3 of COPD, which is FEV 1/FVC < 0.7 or FEV 1 of 30 to 50% predicted. ICS is also initiated in patients with mild persistent asthma and is used throughout the remaining stages but in higher doses.

Design

  • Population-based, longitudinal cohort study
  • Patient data was gathered from the Ontario Registered Persons Database from September 1, 2003 to march 31, 2011.
  • Follow-up: up to 5 years

Population

  • Patients aged 66 years or older with COPD and asthma not receiving an inhaled anticholinergic.
  • N=38266
  • LABAs and ICS= 34289
  • LABAs alone=3258
  • Exclusion= 719
  • Setting: In Ontario, Canada, based on patient demographic and national health care records

Inclusion Criteria

  • Validated case definition of physician-diagnosed COPD
  • Age greater than or equal to 66 years
  • New users of LABA or LABA/ICS between September 1, 2003 to March 31, 2011

Exclusion Criteria

  • Younger than 66 years old
  • Patients without COPD
  • Patients who were already treated with both LABA and ICS
  • Patients ineligible for health insurance
  • Patients who received lung reduction or transplantation

Baseline Characteristics

All information reported as LABA/ICS vs. LABA-alone

  • Mean Age (years): 76 vs. 77
  • COPD and general care:
    • Duration of COPD > 5 years (%): 58.1 vs. 54.4
    • Most recent hospitalization for COPD: > 5 years or never (%): 61.7 vs. 50.1
    • Most recent hospitalization for COPD-related condition: < 5 years or never (%): 79.1 vs. 72.9
    • Median number of general practitioner visits in previous year: 6 vs. 6
    • Median number of medications taken in previous year: 6 vs. 7
    • Visit to a specialist in the past year (%): 45.4 vs. 45.9
  • Comorbidity diagnosed prior to index date:
    • Asthma (%): 32.2 vs.28.9
  • Other COPD medication use in previous year:
    • Long-acting anticholinergic (%): 54.7 vs. 64.8
    • Short-acting anticholinergic (%): 23.3 vs. 43.5
    • Short-acting beta agonist (%): 58.5 vs. 71.4
    • Methylxanthine (%): 2.2 vs.3.7
    • Number of prescriptions for oral steroids: 0 (%): 77.1 vs.76.4
    • Number of prescriptions for antibiotics; ≥ 2 (%): 37.7 vs. 32.2
  • Other medication use in previous year:
    • Angiotensin-converting enzyme inhibitors (%): 41.5 vs. 43.9
    • Beta-blockers (%): 31.8 vs. 31.9
    • Statins (%): 49.5 vs. 42.3

Interventions

Group 1 patients were new users of LABAs and ICS vs. Group 2 were new users of LABAs alone.

Outcomes

Comparisons are combination LABA/ICS therapy vs. LABA therapy.

Primary Outcomes

Death or hospitalization for COPD
57.5% vs. 61.2% (HR 0.92; 95% CI 0.88-0.96; P=<0.001; NNT=27)

Secondary Outcomes

Hospitalization for pneumonia
25.5% vs. 25.7% (HR 1.01; 95% CI 0.93-1.08; P=0.88)
Hospitalization for fracture of hip, wrist or vertebrae
4.9% vs. 4.6% (HR 1.13; 95% CI 0.95-1.35; P=0.17)
Diagnosis of asthma
60.4% vs. 66.8% (HR 0.84; 95% CI 0.77-0.91; P=<0.001; NNT= 16)
No receipt of Long-acting Anti-cholinergics
59.5% vs. 68.4% (HR 0.79; 95% CI 0.73-0.86; P=<0.001; NNT=11)

Subgroup Analysis

For a subgroup who did not have asthma who were not receiving long-acting muscarinic antagonists (LAMAs) and who received LABAs and ICS had a lower risk of the composite outcome of a magnitude similar to people with asthma.In the subgroup of patient who had asthma, the combination LABA/ICS was superior to LABA-alone (60.4 vs. 66.8%; HR 0.84 95%CI 0.77-0.91). However, those who did not have asthma did not show a significant difference (65.7 vs. 67.6%; HR 0.96 95% CI 0.9-1.01). Also in the subgroup of patients who did not receive LAAs, the addition of a LABA-alone was beneficial to patients than compared to the combination of LABA/ICS (59.5 vs. 68.4%; HR 0.79 95% Cl 0.73-0.86). However, those who did receive LAAs took away the benefit of receiving ICS (65.3 vs. 66.4%; HR 1.01 95% Cl 0.95-1.07).

Adverse Events

Not reported

Criticisms

There were limitations addressed in this article such as the exclusion of patients with COPD from the study due to a misclassification based on the health administrative data. Another limitation included patients that were misclassified as not having COPD and were not included in the study but should have been. Although this may be an insignificant difference in the study, it may have lead to a decrease in precision of the overall results. In addition, there are no reports of adverse events in the study, which would have been better to include rather than only showing only the benefits. Lastly, because ICS is a big risk for patients with COPD, including rates of pneumonia for those patients on ICS would have been beneficial data to look at.

Funding

Funding was made available through a Drug Innovation Fund Grant from the Government of Ontario and supported by the Institute for Clinical Evaluative Sciences.

Further Reading

Magnussen H, Watz H, Kirsten A, et al. Stepwise withdrawal of inhaled corticosteroids in COPD patients receiving dual bronchodilation: WISDOM study design and rationale. Respir Med. 2014;108(4):593–599