CAUTION WITH ATROVENT

Drug Used for COPD Linked to Increased Mortality Risk

eptember 19, 2008 — Ipratropium used for chronic obstructive pulmonary disease (COPD) is associated with the risk for all-cause and cardiovascular death, according to the results of a nested case-control study reported in the September 16 issue of the Annals of Internal Medicine.

"Concerns exist regarding increased risk for mortality associated with some...COPD medications," write Todd A. Lee, PharmD, PhD, from the Hines Veterans Affairs Hospital in Hines, Illinois, and the Northwestern University Feinberg School of Medicine in Chicago, Illinois. "The extent to which these safety concerns exist and can be generalized to patients with COPD outside the context of clinical trials is unclear. Therefore, we sought to examine the association between medication use and risk for death, including respiratory and cardiovascular deaths, in a large population of patients with recently diagnosed COPD."

The study cohort of 32,130 case patients and 320,501 control participants was identified between October 1, 1999, and September 30, 2003, and followed up through September 30, 2004, with use of National Veterans Affairs inpatient, outpatient, pharmacy, and mortality databases; Centers for Medicare & Medicaid Services databases; and National Death Index Plus data.

For a random sample of 40% of those who died during follow-up, the cause of death was determined. Case patients were grouped in categories on the basis of all-cause, respiratory, or cardiovascular death. Mortality risk linked to use of COPD medication was determined by conditional logistic regression adjusted for comorbid conditions, healthcare use, and markers of COPD severity.

Relevant exposure was considered to be use of inhaled corticosteroids, ipratropium, long-acting beta-agonists, and theophylline in the 6 months before death. Of 11,897 patients for whom data on cause of death were available, 2405 case patients had respiratory deaths and 3159 case patients had cardiovascular deaths.

For all-cause mortality, adjusted odds ratios (ORs) were 0.80 (95% confidence interval [CI], 0.78 - 0.83) for inhaled corticosteroids, 1.11 (95% CI, 1.08 - 1.15) for ipratropium, 0.92 (95% CI, 0.88 - 0.96) for long-acting beta-agonists, and 1.05 (95% CI, 0.99 - 1.10) for theophylline. Although ipratropium was linked to a greater risk for cardiovascular deaths (OR, 1.34; 95% CI, 1.22 - 1.47), inhaled corticosteroids were associated with a lower risk for cardiovascular death (OR, 0.80; 95% CI, 0.72 - 0.88). Results were consistent across sensitivity analyses.

"The possible association between ipratropium and elevated risk for all-cause and cardiovascular death needs further study," the study authors write.

Limitations of this study include observational design, lack of data on current smoking status and lung function, and unknown misclassification of cause-specific mortality.

"Ipratropium may increase the risk for cardiovascular death; however, this risk may be attenuated by the concomitant use of inhaled corticosteroids, which were associated with reduction in the risk for all-cause and cardiovascular death," the study authors conclude. "The risk for death due to some medications must be weighed against potential benefits of these medications that are not captured in observational database studies, such as symptom relief, health status, or quality of life. It is not clear, however, that these benefits would outweigh the increased risk for death."