Tiotropium Respimat increases the risk of mortality
- 1Airways Group, Woolcock Institute of Medical Research, Camperdown, Australia
- 2Medical Research Institute of New Zealand, Wellington, New Zealand
- Correspondence to Professor Christine R Jenkins, Department of Thoracic Medicine, Concord Hospital, Hospital Road, Concord, NSW 2139, Australia;
- Accepted 25 October 2012
In the 10 years since tiotropium was introduced into clinical practice, it has become the mainstay long-acting bronchodilator for maintenance treatment in Chronic Obstructive Pulmonary Disease (COPD). Multiple randomised controlled trials have demonstrated its efficacy as an intervention which improves lung function, quality of life, symptom control and exercise capacity, and reduces exacerbations in patients with COPD.1
Subsequent to the introduction of tiotropium, evidence emerged from the Lung Health Study that ipratropium, the short-acting anticholinergic medication widely used prior to tiotropium, was associated with a greater risk of cardiac death in the smoking intervention-ipratropium (SI-A) arm compared with the smoking intervention-placebo (SI-P) arm.2 There was a preponderance of arrhythmias as a cause of hospitalisation in the SI-A group because of a relatively high prevalence of supraventricular tachycardia. Because smoking cessation rates were similar in both groups, ipratropium looked to be the likely cause.
Following this, the United States Food and Drug Administration, being made aware of an increased risk of stroke in pooled data from 29 trials of tiotropium through a report supplied to it by the manufacturer, issued an early warning in March 2008.3 Later that year, a meta-analysis of 17 trials (ipratropium (n=5) and tiotropium (n=12)) showed an increased risk of the primary composite endpoint of cardiovascular death, myocardial infarction or stroke (relative risk 1.60, 95% CI 1.22 to 2.10) and of all-cause mortality (relative risk 1.29, 95% CI 1.00 to 1.65).4 Inhaled anticholinergics significantly increased the risk of myocardial infarction (relative risk 1.52, 95% CI 1.04 to 2.22) and cardiovascular death (relative risk 1.92, 95% CI 1.23 to 3.00), but not stroke (relative risk 1.46, 95% CI 0.81 to 2.62).
However, also later in 2008 the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study,5 the largest randomised trial of tiotropium, showed …