Outcomes Associated with Salmeterol Use in Obstructive Lung Disease
Todd A. Lee PhD PharmD
Edward Hines Jr. VA Hospital, Hines, IL
Funding Period: October 2004 - September 2007
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.
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.
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.
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.
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.
DRE: Treatment - Observational
Keywords: Chronic lung disease, Pharmaceuticals, Quality assessment
MeSH Terms: none