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IIR 03-307 – HSR&D Study

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IIR 03-307
Outcomes Associated with Salmeterol Use in Obstructive Lung Disease
Todd A. Lee PhD PharmD
Edward Hines Jr. VA Hospital, Hines, IL
Hines, IL
Funding Period: October 2004 - September 2007

BACKGROUND/RATIONALE:
Patients with obstructive lung disease, either asthma or chronic obstructive pulmonary disease (COPD), frequently suffer from shortness of breath as a result of their disease. Treatment with inhaled beta-adrenergic agonists (beta-agonists) offers relief from these symptoms. The long-acting beta-agonist formulations currently available in the United States are salmeterol (Serevent and Advair) and formoterol (Foradil) and both have approved indications for treatment of patients with asthma and COPD. However, there are concerns about the safety of these medications in patients with asthma and their benefit in patients with COPD. Results from a large post-marketing study indicated there was an increased risk of asthma-related deaths in patients treated with salmeterol and the risk was potentially greater in African-American patients than in Caucasian patients. In patients with COPD, there is limited evidence on the outcomes associated with long-term use of long-acting beta-agonists.

OBJECTIVE(S):
The objective of this study was to examine the outcomes of patients with asthma or COPD that used a long-acting beta-agonist product with those that have not been exposed to long-acting beta-agonists. The specific aims of the project were: 1) determine the all-cause and respiratory-specific mortality associated with exposure to long-acting beta-agonists in VA patients with asthma, COPD or both; 2) determine the rate of respiratory-related life-threatening experiences (e.g. placed on ventilator) between long-acting beta-agonist users and non-users; and 3) compare the exacerbation rates and healthcare resource utilization in patients exposed to beta-agonists versus those not exposed.

METHODS:
We conducted an observational cohort study in VA patients with a diagnosis of asthma, COPD or both between FY1999 and FY2004 to evaluate the outcomes associated with long-acting beta-agonist use. We used VA healthcare utilization and pharmacy data, as well as National Death Index (NDI) data in conducting this analysis. The patient cohort was identified using national inpatient and outpatient data. Medication exposure was identified from the PBM database. Patients were followed from their initial diagnosis until date of death, the end of the study period or until they are lost to follow-up. Deaths were identified using the VA Vital Status File data and cause of death determined using NDI Plus data. We evaluated the risk of death associated with exposure to long-acting beta-agonists in each of the three study cohorts. We also conduct a nested case-control study in patients with respiratory-related or cardiovascular-related cause of death to evaluate the association between exposure and cause-specific mortality. Finally, we evaluated the exacerbation rates and healthcare utilization, comparing exposed and unexposed patients.


FINDINGS/RESULTS:
In examining the risk of LABAs and all cause mortality, we found that there was an increased risk of all cause mortality associated with LABA use. The crude (unadjusted) and adjusted relative risk for all-cause mortality, comparing patients 'exposed' vs. 'unexposed' to LABAs, was 1.41 (95% CI 1.34 to 1.49) and 1.07 (1.01-1.14) respectively. The risk was mitigated by the concomitant use of inhaled corticosteroids. While point estimates suggested a trend of more than a 10% increase in risk of respiratory-related deaths associated with LABA (OR = 1.12 [0.97-1.30]) it was not statistically significant. We found there was an increased risk of cardiovascular events (CVEs) in patients exposed to ipratropium. Ipratropium exposure was associated with a 34% increase in the likelihood of a cardiovascular death (OR = 1.34 [1.22-1.47]). The estimated number needed to treat for one year to cause one additional cardiovascular death with ipratropium was 261 patients.


IMPACT:
Our findings still raise questions about LABA safety in patients with COPD and warrant continued caution on the part of clinicians. These findings need to be considered and weighed with evidence of decreased exacerbations and improved quality of life associated with the use of LABAs. However, the more important consideration for treating newly diagnosed patients with COPD is the apparent increased risk of cardiovascular events associated with ipratropium. It is important that clinicians and those responsible for VA guidelines consider this when making recommendations, as the increased risk of cardiovascular events likely outweigh any benefits associated with ipratropium.


PUBLICATIONS:

Journal Articles

  1. Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. Cardiovascular events associated with ipratropium bromide in COPD. Chest. 2010 Jan 1; 137(1):13-9.
  2. Joo MJ, Au DH, Lee TA. Use of spirometry in the diagnosis of chronic obstructive pulmonary disease and efforts to improve quality of care. Translational research : the journal of laboratory and clinical medicine. 2009 Sep 1; 154(3):103-10.
  3. Jung E, Pickard AS, Salmon JW, Bartle B, Lee TA. Medication adherence and persistence in the last year of life in COPD patients. Respiratory medicine. 2009 Apr 1; 103(4):525-34.
  4. Pickard AS, Jung E, Bartle B, Weiss KB, Lee TA. Coded cause of death and timing of COPD diagnosis. COPD. 2009 Feb 1; 6(1):41-7.
  5. Joo MJ, Lee TA, Au DH, Fitzgibbon ML, Weiss KB. Medication use patterns associated with spirometry in diagnosing COPD. COPD. 2008 Dec 1; 5(6):360-8.
  6. Lee TA, Pickard AS, Au DH, Bartle B, Weiss KB. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Annals of internal medicine. 2008 Sep 16; 149(6):380-90.
  7. Lee TA, Shields AE, Vogeli C, Gibson TB, Woong-Sohn M, Marder WD, Blumenthal D, Weiss KB. Mortality rate in veterans with multiple chronic conditions. Journal of general internal medicine. 2007 Dec 1; 22 Suppl 3:403-7.
  8. Vogeli C, Shields AE, Lee TA, Gibson TB, Marder WD, Weiss KB, Blumenthal D. Multiple chronic conditions: prevalence, health consequences, and implications for quality, care management, and costs. Journal of general internal medicine. 2007 Dec 1; 22 Suppl 3:391-5.
  9. Lee TA, Pickard AS, Bartle B, Weiss KB. Osteoarthritis: a comorbid marker for longer life? Annals of epidemiology. 2007 May 1; 17(5):380-4.
  10. Lee TA, Bartle B, Weiss KB. Spirometry use in clinical practice following diagnosis of COPD. Chest. 2006 Jun 1; 129(6):1509-15.
Conference Presentations

  1. Lee TA, Pickard AS, Au D, Bartle B, Weiss KB. Medication Safety in COPD Patients: The Risk of Mortality Associated with Treatment in Veterans with Newly Diagnosed COPD. Paper presented at: American College of Chest Physicians Annual International Scientific Assembly (CHEST); 2009 Oct 28; Philadelphia, PA.
  2. Lee TA, Pickard AS, Bartle B, Weiss KB. COPD medication safety: risk of respiratory and cardiovascular deaths associated with treatment. Poster session presented at: American Thoracic Society Annual International Conference; 2008 May 1; Toronto, Canada.
  3. Lee TA, Ogale SS, Sulivan SD, Au D. Risk of All-Cause Mortality Associated with Long-Acting Beta-Agonist Use in Veterans with COPD. Paper presented at: VA HSR&D National Meeting; 2008 Feb 15; Baltimore, MD.
  4. Lee TA, Pickard AS, Bartle B, Weiss KB. Medication Safety in COPD Patients: The Risk of Respiratory and Cardiovascular Deaths Associated with Treatment in Veterans with COPD. Paper presented at: VA HSR&D National Meeting; 2008 Feb 14; Baltimore, MD.
  5. Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. Cardiovascular outcomes associated with anticholinergic medications. Poster session presented at: American Thoracic Society Annual International Conference; 2007 May 1; San Francisco, CA.
  6. Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. Long-acting beta2-agonists and all-cause mortality in COPD. Poster session presented at: American Thoracic Society Annual International Conference; 2007 May 1; San Francisco, CA.
  7. Ogale SS, Lee TA, Sullivan SD. The risk of cardiovascular events associated with inhaled long-acting beta-2-adrenoreceptor agonists in patients with chronic obstructive pulmonary disease. Poster session presented at: American College of Chest Physicians Annual International Scientific Assembly (CHEST); 2006 Oct 1; Salt Lake City, UT.
  8. Pickard AS, Lee TA, Bartle B, Weiss KB. Medication Use and Causes of Death in Veterans with COPD: A Large Database Study. Poster session presented at: Midwest Pharmacy Administration Annual Meeting; 2006 Jul 1; Minneapolis, MN.
  9. Lee TA, Pickard AS, Bartle B, Weiss KB. Prescription for longer life: a diagnosis of osteoarthritis? Poster session presented at: International Society for Pharmacoeconomics and Outcomes Research Annual Meeting; 2006 May 1; Philadelphia, PA.


DRA: none
DRE: Treatment - Observational
Keywords: Chronic lung disease, Pharmaceuticals, Quality assessment
MeSH Terms: none