Cardiac Safety of Tiotropium in Patients With Cardiac Events

A Retrospective Analysis of the Uplift Trial

Donald P Tashkin; Inge Leimer; Norbert Metzdorf; Marc Decramer


Respiratory Research. 2015;16(65) 

In This Article

Abstract and Introduction


Background: Tiotropium is an anticholinergic bronchodilator for symptom relief and reducing exacerbations with an established safety profile in patients with chronic obstructive pulmonary disease (COPD). Using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study, we re-evaluated the safety of tiotropium HandiHaler® in patients who experienced recent myocardial infarction (MI), heart failure or unstable rhythm disorder during the study.

Methods: A post-hoc analysis of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, was conducted in patients who had experienced cardiac arrhythmia, MI or cardiac failure during UPLIFT® and who completed the study. Descriptive analyses were performed.

Results: Most patients experiencing cardiac events, for which they would have been excluded at baseline, remained in the trial. Kaplan-Meier analyses revealed a trend to later occurrence of cardiac SAEs with tiotropium HandiHaler® versus placebo. Patients who experienced a cardiac event and continued in UPLIFT® were not found to be at subsequently increased risk of all-cause mortality or cardiac SAEs with tiotropium treatment. Evaluation of deaths by major adverse cardiac events composite endpoints also showed that patients treated with tiotropium were not at increased risk of mortality or cardiac SAEs compared with placebo.

Conclusions: Risk of cardiac events, mortality or SAEs was not increased by tiotropium in patients experiencing cardiac events for which they would have been excluded at study baseline. The findings support the cardiac safety of tiotropium HandiHaler® in patients with COPD.


Tiotropium is a once-daily maintenance anticholinergic bronchodilator for the relief of symptoms and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD).[1–3] Two formulations have been developed (SPIRIVA®, Boehringer Ingelheim, Ingelheim am Rhein, Germany): tiotropium HandiHaler® 18 μg once daily, a dry powder inhaler; and tiotropium Respimat® 5 μg (two puffs of 2.5 μg) once daily. Respimat® was developed to provide a more efficient drug delivery system, with increased deposition in the lung to allow for a reduced nominal dose versus Handihaler®, a delivered dose independent of inspiratory effort and ease of co-ordination of actuation and inhalation.[4,5] Pharmacokinetic analysis indicates that systemic exposure is similar for tiotropium 18 μg via HandiHaler® and tiotropium 5 μg via Respimat®;[6,7] clinical studies have also shown that the Tiotropium Respimat® is non-inferior to HandiHaler® for lung function outcomes and rescue medication use,[6,7] as well as exacerbation risk.[8]

A reduction in mortality versus placebo was observed in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study, a randomised, double-blind trial in which tiotropium HandiHaler® was compared with placebo in almost 6000 patients over a period of 4 years.[9] In this study, for the protocol-defined study period up to Day 1440, among patients for whom vital status information was available, 921 patients died: 14.4% in the tiotropium group, 16.3% in the placebo group (hazard ratio: 0.87; 95% confidence interval [CI]: 0.76–0.99).[9] In line with the findings from UPLIFT®, other meta-analyses and data reviews have also failed to find any increases in all-cause mortality in patients with COPD.[10–13]

However, safety concerns were raised when a post-hoc pooled analysis of three 1-year and one 6-month placebo-controlled trials found that tiotropium Respimat® 5 μg was associated with a higher number of fatal events than placebo, although the difference was not statistically significant. The difference was particularly found in patients with cardiac rhythm disorders at randomisation.[14] The contribution of a rhythm disorder to the fatal outcome was uncertain and a causal relationship with tiotropium Respimat® has not been established. Subsequent systematic reviews and meta-analyses of the same clinical dataset by different authors have also described an increase in mortality associated with Respimat®.[15–17] However, the TIOtropium Safety and Performance In Respimat® (TIOSPIR™) study found no difference in mortality with tiotropium Respimat® versus HandiHaler® with respect to the risk of death, and causes of death were similar between the groups.[8]

The debate surrounding potential differential effects of HandiHaler® and Respimat® on mortality associated with tiotropium has led to discussion and re-evaluation of previous clinical trials in COPD to understand the validity of the findings. Most recently, the generalisability of the results of the 4-year UPLIFT® trial comparing tiotropium with placebo was called into question, based on potential eligibility of a hospitalised patient population with COPD in New Zealand for UPLIFT®.[18] In their evaluation of 100 patients who were prescribed tiotropium, the authors concluded that 38% (95% CI: 28.5–48.3) would have been ineligible for UPLIFT® at the time of hospital discharge due to recent cardiovascular (CV) co-morbidity or moderate to severe renal impairment. While the interpretation of the findings from this study were challenged by the authors of UPLIFT®,[19] it was recognised that analysis of outcomes of patients experiencing cardiac events during the 4-year UPLIFT® study could add valuable data to the debate on the potential effects of tiotropium on CV and overall mortality. It has recently been noted that, in addition to looking at overall mortality or composite CV endpoints (such as major adverse CV events [MACE]), specific cardiac outcomes (such as myocardial infarction [MI]) should also be considered, to avoid masking a potential treatment effect on a particular type of event.[20]

Patients experiencing specific recent cardiac events before the baseline of UPLIFT® were excluded from participation in the trial. Therefore, to evaluate tiotropium HandiHaler® safety in patients with recent cardiac events, we conducted post-hoc analyses of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, in patients who experienced cardiac arrhythmia, MI or cardiac failure during the conduct of the UPLIFT® study.