Chicago, IL - Patients with chronic obstructive pulmonary disease (COPD) who used inhaled anticholinergic agents for at least a month, compared with controls who took placebo or other inhaled agents, showed a significant 58% independent increase in risk of CV death, MI, or stroke in a 17-trial meta-analysis appearing in the September 24, 2008 issue of the Journal of the American Medical Association [1]. Their risk of CV death alone jumped 80%, although such events were few in the populations studied.

Most of the excess risk appeared to come from studies in which the drugs, ipratropium bromide (Atrovent or, combined with albuterol, Combivent, Boehringer-Ingelheim) and tiotropium bromide (Spiriva, Pfizer/Boehringer-Ingelheim), were taken for at least six months.

Physicians and their patients with COPD should take the findings into account "and decide whether these risks are an acceptable trade-off in return for their symptomatic benefits," write the authors of the analysis, led by Dr Sonal Singh (Wake Forest University, Winston-Salem, NC).

"I think this is a public-health issue," Singh said to heartwire, noting that the analysis is likely stronger than some earlier, more limited observational analyses of inhaled anticholinergic use in COPD that had not found such risks. And in clinical practice, suggestions of increased CV risk may go unnoticed because they are masked by the COPD, he speculated, noting that cardiac death is already the most common form of death in COPD.

There's been a fear . . . that these drugs might induce arrhythmias or strokes, and this has worried some doctors. Having said that, the analysis of data not collected for that specific purpose usually must be taken as hypothesis-generating.

"Maybe we weren't paying attention early on, but maybe now we should pay attention to this cardiovascular risk and inform doctors and patients, and maybe some patients should use alternative medications," he said. The decision would be made on a case-by-case basis, as the symptom relief inhaled anticholinergics provide may be more important to some COPD patients than others, especially if they don't already have other CV risk factors. But, Singh added, "maybe, for people who are at high risk for cardiovascular disease, [long-term inhaled anticholinergics] are not the appropriate therapy."

Commenting on the new analysis for heartwire, Dr Bartolome R Celli (Tufts University School of Medicine, Boston, MA) said it's "interesting, because there's been a fear in the clinical community that these drugs might induce arrhythmias or strokes, and this has worried some doctors who treat patients with COPD. Having said that, the analysis of data not collected for that specific purpose usually must be taken as hypothesis-generating."

Lacking a randomized trial, he noted, "you can't really determine whether what you're seeing is just from bias or from operative definitions that were not meant to be in a prospective trial." Celli, who is not connected with the Singh et al analysis, is chief of pulmonary and critical care medicine at Boston's St Elizabeth's Medical Center.

He emphasized that CV death events in the meta-analysis were few, suggesting, potentially, that any such increased risk may not be that clinically important despite reaching statistical significance. Still, he said, the analysis provides important information, and based on it, he might, for example, recommend against inhaled anticholinergics in a COPD patient with arrhythmias or not give them to one with a history of stroke.

Singh et al screened 17 randomized trials encompassing 14 783 patients, who were followed for six weeks to five years; they included published studies as well as unpublished data obtained from government and corporate sources. To be included, the trials had to follow COPD patients taking either of the inhaled anticholinergics or a control therapy, which could include placebo or inhaled beta agonists with or without a steroid, for at least 30 days; trials that included patients with asthma were excluded.

The relative risk of death from any cause was increased by 26% among those taking the agents, which fell short of significance (p=0.06).

A sensitivity analysis of only the five trials that followed patients for at least six months yielded a relative risk for the composite end point of 1.73 (95% CI 1.27-2.36, p<0.001) against those on inhaled anticholinergics, Singh et al report.

Other analyses showed that the composite risk was significantly increased in the long-term trials for both ipratropium (RR 1.57, 95% CI 1.08-2.28; p=0.02) and tiotropium (RR 2.12, 95% CI, 1.22-3.67; p=0.008) individually.

Celli said he's looking forward to the upcoming release of findings from the four-year, randomized controlled Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study of >6000 patients with COPD, "which is testing this hypothesis prospectively." If the findings of Singh et al are confirmed in UPLIFT, he said, "they will have a lot of validity." If they are not, "then you can think of a thousand reasons why [their analysis] turned out the way it did."

Singh et al caution, however, that UPLIFT "has not been specifically designed to address cardiovascular adverse events and may not provide information on nonfatal cardiovascular adverse events, as well as the cardiovascular adverse effects of inhaled ipratropium."