Anticholinergics and Cardiovascular Safety

Increasingly, the cardiovascular safety of commonly prescribed drugs has been brought into question with the notable recent examples of the COX-2 inhibitors and the thiazolidinediones.  Among the most frequently prescribed inhaled medications for COPD, a common condition in patients with coronary disease due to the shared aetiology of cigarette smoking, are anticholinergic agents such as short-acting ipratropium bromide, available for 20 years, and the long-acting drug tiotropium bromide, introduced only in 2002.  For several years now a link between anticholinergic drugs and an increased risk of cardiovascular mortality has been reported and debated with the short acting drugs felt to be harmful while paradoxically, tiotropium may even be protective, although there seems no reasonable explanation based on their pharmacology.  Two new studies look at this issue.  

In the first, the authors present data from a cohort study of 82,717 US veterans with a new diagnosis of COPD established between 1999 and 2002.  Subjects were followed until they had their first hospitalization for events such as acute coronary syndrome, heart failure, or cardiac dysrhythmia, or until death and cumulative ipratropium exposure was calculated.  The study identified 6,234 cardiovascular events, and compared with subjects not exposed to ipratropium within the past year, any exposure to ipratropium within the past 6 months was associated with a significantly increased risk of a cardiac event (HR 1.4 (1.3-1.51)).  The second study presents data from the clinical trial safety database for tiotropium. A total of 19,545 patients, (10,846 on tiotropium and 8,699 on placebo) from 30 prospective trials were included with a cumulative exposure to tiotropium and placebo of 13,146 and 11,095 patient-years, respectively.  Incidence rates were determined for all-cause mortality and selected cardiovascular events, such as cardiovascular deaths, nonfatal myocardial infarction, nonfatal stroke, and sudden death.  For all-cause mortality, the incidence rate was 3.44 for tiotropium and 4.10 for placebo per 100 patient-years, and the other incidence rates all favored tiotropium over placebo.  While the first study has a number of limitations, pertaining to its retrospective design, it nevertheless adds to the persisting concern about short-acting anticholinergics and cardiovascular safety.  The tiotropium clinical trial program meanwhile represents a substantial prospective database, and the results act as strong confirmatory data that tiotropium reduces the risk for cardiovascular events and cardiovascular mortality.

Conclusions:
Long-acting tiotropium appears to be safe in cardiovascular patients, whereas retrospective large cohort analyses have consistently concluded that the short-acting ipratropium has a small but consistent effect on cardiovascular events.  It remains important for clinicians and patients to be aware of the potential benefits as well as the cardiovascular risks when making medication decisions for the treatment of COPD.

Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. Cardiovascular events associated with ipratropium bromide in COPD. Chest. 2010 Jan;137(1):13-9.
Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin DP. Cardiovascular safety of tiotropium in patients with COPD. Chest. 2010 Jan;137(1):20-30.

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