Level 2: Mid-level evidence

A systematic review evaluated 17 randomized trials (with methodologic limitations) of any inhaled anticholinergic (ipratropium [Atrovent] and tiotropium [Spiriva]) for >30 days compared with placebo or active control in 14,783 patients with chronic obstructive pulmonary disease (COPD) (JAMA. 2008;300:1439-1450). Inhaled ipratropium was evaluated in five trials; inhaled tiotropium was evaluated in 12 trials. Follow-up ranged from six weeks to five years.

Compared with control, anticholinergics were associated with higher rates of cardiovascular death in analysis of 12 trials with 12,376 patients (0.9% vs. 0.5%, P =.008, NNH 250), MI in analysis of 11 trials with 10,598 patients (1.2% vs. 0.8%, P =.03, NNH 250), and all-cause mortality in analysis of 17 trials with 14,783 patients (2% vs. 1.6%, P =.06, NNH 250). There were no significant differences in rate of stroke in analysis of seven trials with 9,251 patients (0.5% vs. 0.4%). Ipratropium was associated with higher rates of the composite outcome (cardiovascular death, MI, and stroke) compared with control (2.5% vs. 1.5%, P =.003, NNH 100); tiotropium was associated with a nonsignificant trend (1.3% vs. 0.96%, P =.08).

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