Inhaled anticholinergics in COPD and cardiovascular risk

• a meta-analysis of 17 randomised controlled trials (RCTs) suggests that inhaled anticholinergic drugs (ipratropium, tiotropium) increase the risk of cardiovascular (CV) events in people with chronic obstructive pulmonary disease (COPD) compared with placebo or active comparators (inhaled corticosteroids and/or beta-agonists) (1)
  • provides the possibility of increased CV risk with inhaled anticholinergics in people with COPD, but this cannot be regarded as definitive (3)
    • from other studies, the number needed to treat (NNT) with tiotropium to prevent one exacerbation was estimated to be 21 (95% confidence interval [CI] 13 to 50), and for COPD-related hospitalisation it was around 20 (95% CI 14 to 34) per year compared with placebo
    • needs to be balanced against a number needed to harm (NNH) for myocardial infarction (MI) of 174 (95% CI 75 to 1835) per year with inhaled tiotropium or ipratropium - assuming a baseline MI event rate of 10.9 per 1000 person years (3)
• however, the precise magnitude of this increased risk is uncertain
  • in addition, results from the UPLIFT randomised controlled trial provide limited reassurance about the CV risk of tiotropium (2)
    • in the UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) study (n=5,993) there were no statistically significant differences in the risk of MI (RR 0.73, 95% CI 0.53 to 1.00) or stroke (RR 0.95, 95% CI 0.70 to 1.29) compared with placebo
      • however the trial was not designed to look at any CV endpoints, so there may have been differences in how these outcomes were reported
  • the UPLIFT study did show that in patients with COPD, most of whom were taking long acting beta agonists and inhaled steroids, that tiotropium improved quality of life and reduced exacerbations but did not reduce the rate of decline of FEV1 (2)
• a review (3) concluded that "..uncertainty still exists regarding the CV safety of inhaled anticholinergics in people with COPD.."
• the MHRA have concluded that these conflicting findings make it difficult to draw firm conclusions on the risk of all-cause mortality, CV death, or stroke associated with inhaled anticholinergics, and further analyses are needed to shed light on any possible increased risk (4)

Reference:

• 1. Singh S et al. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA 2008;300:1439?50
• 2. Tashkin DP et al. A 4-year trial of tiotropium in Chronic Obstructive Pulmonary Disease. N Engl J Med 2008;359:1543?54
• 3. MeReC Monthly No.8 November 2008.
• 4. MeReC Bulletin 2009; 19 (4).