Tiotropium Respimat increases the risk of mortality.

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. Subsequent to the introduction of tiotropium, evidence emerged from the Lung Health Study that ipratropium, the shortacting 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. 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. 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). 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, the largest randomised trial of tiotropium, showed that in comparison with placebo tiotropium was not associated with an increased risk of mortality (HR 0.89, 95% CI 0.79 to 1.02), myocardial infarction (relative risk 0.73, 95% CI 0.53 to 1.00) or stroke (relative risk 0.95, 95% CI 0.70 to 1.29). Although not adjusted for multiple comparisons, a sensitivity analysis showed a statistically significant reduction in all-cause mortality at the end of the protocol-defined treatment period. These reassuring findings together with the reduction in COPD exacerbations and improvement in lung function and quality of life contributed to a favourable efficacy/safety profile being established for tiotropium. However, the reassurance was tempered by recognition that subjects at the greatest risk of cardiovascular events (moderate to severe renal impairment or a recent history of myocardial infarction, unstable or lifethreatening cardiac arrhythmias, or hospitalisation with heart failure) were excluded from the study, thereby limiting the generalisability of the findings. Into this uncertainty entered a new device, the Respimat, a fine mist inhaler delivering the tiotropium dose independently of inspiratory effort and patient coordination, and with the potential benefits of a small aerosol particle size and hence more uniform delivery to smaller airways. In 2011, the British Medical Journal (BMJ) published a systematic review and meta-analysis of randomised placebo-controlled trials of tiotropium solution using the mist inhaler (tiotropium Respimat) in the treatment of COPD. It reported a 50% increased risk of mortality with tiotropium Respimat. To gain insight into the clinical and public health significance of these findings, it is worthwhile examining the study in more detail, the critiques that have been proposed, the potential mechanisms of the effect and further data that have been published in the 12 months since its publication. The systematic review and metaanalysis included all parallel group, randomised, placebo-controlled trials of tiotropium Respimat in the treatment of COPD that reported data on mortality and were of at least 30 days duration. The relative risk of all-cause mortality was estimated using a fixed effect metaanalysis and heterogeneity was assessed with the I statistic. In total, five trials were included, two of 12 weeks and three of 12 months duration, with a total of 6522 subjects studied. Tiotropium Respimat significantly increased the risk of all-cause mortality (relative risk 1.52, 95% CI 1.06 to 2.16, p=0.02, I=0%) and cardiovascular death (relative risk 2.05, 95% CI 1.06 to 3.99). The findings were suggestive of a dose–response effect on all-cause mortality with relative risks of 1.46 (95% CI 1.01 to 2.10) and 2.15 (95% CI 1.03 to 4.51) estimated for the 5 and 10 g preparations, respectively. The overall estimates were not substantially changed by sensitivity analyses using the random effects model, limiting the analysis to three trials of 1 year’s duration each, or the inclusion of additional preliminary data on tiotropium Respimat from an unpublished study. In an accompanying editorial it was calculated that one excess death could be expected for every 121 patients with COPD treated with the 5 g dose by Respimat for 12 months. Six main criticisms have been advanced regarding the meta-analysis and its interpretation. 11 First, Boehringer Ingelheim, the manufacturer of tiotropium Respimat, challenged the validity of the analyses; however, two independent systematic reviews and meta-analyses undertaken since the original BMJ publication have reported a similar significant increased risk of all-cause mortality with tiotropium Respimat. 12 The Cochrane Database of Systematic Reviews reported a Peto’s OR of 1.47 (95% CI 1.04 to 2.08) and the recent systematic review and mixed treatment comparison meta-analysis of Dong and colleagues reported an OR of 1.51 (95% CI 1.06 to 2.19). Thus, it is reasonable to conclude that the findings of the original BMJ publication are robust. The second critique that the data relating to the 10 g tiotropium Respimat preparation should not be included in the primary analysis because it is not marketed contradicts the Cochrane Handbook which recommends the amalgamation of all relevant treatment arms into one group. The findings relating to the 10 g tiotropium Respimat preparation also allow investigation of a potential dose–response ▸ http://dx.doi.org/10.1136/thoraxjnl-2012-201926 ▸ http://dx.doi.org/10.1136/thoraxjnl-2012-202071 ▸ http://dx.doi.org/10.1136/thoraxjnl-2012-202483