In 2008, concerns were raised about the cardiovascular and cerebrovascular safety of tiotropium HandiHaler® based on:
1. a report to the FDA from Boehringer Ingelheim, about pooled data from 29 placebo-controlled trials showing an increased risk of stroke in patients treated with tiotropium.
2. a meta-analysis and a case-control study reporting an increased risk of mortality and/or cardiovascular events in patients who received inhaled anticholinergics (ipratropium or tiotropium).
Boehringer Ingelheim also reported an increased risk of mortality with tiotropium Respimat® SMI device based on data from 3 one-year placebo controlled trials. In January 2010, the FDA warning on the use of tiotropium Handihaler® was overruled, based on data from the UPLIFT study and an updated meta-analysis stating that the available data did no longer support an association between the use of tiotropium Handihaler® and an increased risk of stroke, heart attack or death from cardiovascular causes. However, concerns about the safety of tiotropium Respimat remained and a meta-analysis in 2011 based on data from 5 RCTs showing a 50% increased risk of mortality of tiotropium Respimat® SMI compared to placebo. Since then, new data from another meta-analysis comparing the safety of inhaled drugs in patients with COPD reported an increased risk of mortality in patients treated with tiotropium Respimat® SMI vs. tiotropium HandiHaler®.
The current data do not allow definitive conclusions to be drawn on the risk of mortality in patients treated with tiotropium Respimat® compared to tiotropium Handihaler® as no direct head to head comparisons have been conducted to date. This observational cohort study compared the risk of mortality in patients treated with tiotropium Respimat® using tiotropium HandiHaler® as reference category. Data were obtained from a population-based longitudinal observational database containing the complete computer-based medical records of more than 400 GPs in the Netherlands, who voluntarily chose to supply data to the database. A source population of patients, ≥40 years, with at least 1 year of follow-up and episodes of tiotropium use (Respimat® or Handihaler®) based on prescription data, were defined.
From the source population, 11,287 patients provided 24,522 episodes of tiotropium use. A total of 496 patients died while being exposed to Handihaler® or Respimat®. Use of Respimat® was associated with almost 30% increased risk of dying (adjusted hazard ratio, 1.27, 95% CI, 1.03 to 1.57) with the highest risk for cardiovascular/cerebrovascular death (1.56; 1.08 to 2.25). The risk was higher in patients with co-existing cardiovascular disease (1.36; 1.07 to 1.73) than in patients without (1.02; 0.61 to 1.71).
The researchers conclude that use of tiotropium Respimat® was associated with an almost 30% increase in mortality compared to Handihaler® but it is unclear whether this association is causal or due to residual confounding by COPD severity. They note that being observational in nature, their study is sensitive to bias and confounding. Furthermore, due to the nature of the database, exposure was based on prescription data rather than on actual drug intake. Boehringer Ingelheim is currently conducting the TIOSPIR trial, a large international safety study to elucidate the risk of mortality in patients treated with tiotropium Respimat® SMI, using tiotropium HandiHaler® as reference category. This study enrolled up to 17,000 patients who are followed up over 2 years and results are expected in 2014. The researchers recommend that until further data become available, clinicians “should be aware that COPD patients with arrhythmia or a history of cardiovascular disease might be particularly at risk.”
One of the researchers told Reuters that no one knows what might be behind the increased risk with Respimat SMI, adding that "originally it was believed that the systemic effect of Respimat is higher than that of tiotropium Handihaler based on pharmacokinetic studies showing higher plasma concentrations of tiotropium Respimat 5 mcg," she said. However, the data are conflicting as the most recent (pharmacokinetics) study reported lower plasma concentrations for Respimat 5 mcg vs tiotropium Handihaler. The association, if real, needs to be further elucidated."