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


The UPLIFT® study confirmed the CV safety of tiotropium over 4 years for the population included.[10,21] The extensive, long-term patient data generated from the UPLIFT® study have allowed us to investigate retrospectively the potential impact of tiotropium versus placebo on the safety of patients experiencing the types of cardiac events during the study that would have led to exclusion at baseline. The analysis of SAEs or FAEs, including cardiac deaths and death for unknown reasons, in patients after experiencing cardiac arrhythmia, MI or cardiac failure during the conduct of UPLIFT® does not indicate any increase in total or cardiac SAEs or mortality with tiotropium HandiHaler® treatment compared with placebo.

The findings should ameliorate the concerns raised by Walker and colleagues regarding the generalisability of the results of the UPLIFT® trial, based on their analysis of a hospitalised population of patients with COPD in New Zealand.[18] Although patients with unstable or life-threatening cardiac arrhythmias, recent acute MI or severe heart failure requiring hospitalisation were excluded from UPLIFT® (in line with most long-term COPD trials designed to evaluate chronic benefit to risk of pharmacotherapy), but they were not required to withdraw from the study if such an event occurred. The majority of these patients remained in the trial, even though approximately 60% had an SAE and 20% had a cardiac SAE, with similar incidences in the tiotropium and placebo arms. Through the analysis of outcomes in these patients, we are able to show that tiotropium does not increase the risk of total or cardiac SAEs or mortality compared with placebo in patients who have previously experienced serious cardiac events.

It should also be noted that the hospitalised population described by Walker and colleagues[18] – in which 38% would have been ineligible for UPLIFT® at the time of discharge due to recent CV co-morbidity or moderate to severe renal impairment – may not be representative of the general COPD population. In a recent epidemiological analysis from the Netherlands (mean age 68 years), only 2.1% of patients starting treatment with tiotropium HandiHaler® had a COPD-related hospitalisation in the preceding year.[22] In addition, in an analysis of an elderly Canadian population (aged ≥66 years), only 9.8% were recently hospitalised for a respiratory condition and only 1.3% of patients were hospitalised for acute coronary syndrome, including MI, during the 6 months preceding the analysis.[23] Respective percentages were 0.2% for arrhythmias and 2.2% for heart failure. These findings suggest that the incidence of the conditions excluding patients from the initial inclusion in the UPLIFT® study is relatively low.

This analysis has strengths and weaknesses. One obvious weakness is that it is a post-hoc analysis with no hypothesis testing. However, the data from this analysis do not suggest a safety issue in patients with the respective cardiac conditions. Furthermore, a minority of patients dropped out due to the first cardiac event. In general, there was a trend towards fewer patients dropping out in the tiotropium group, limiting potential bias in favour of tiotropium. Strengths of the analysis are that it is derived from a randomised, double-blind study, which reduces the probability of bias in epidemiological analyses where effects arising from prognostic differences among patient groups are a major concern. Finally, the long, 4-year duration of UPLIFT® offered a unique opportunity to investigate the safety of tiotropium in patients with acute major cardiac events who remained in the study.

From this post-hoc analysis of the UPLIFT® trial data, we conclude that tiotropium HandiHaler® does not increase the risk of cardiac deaths, deaths unknown or other cardiac SAEs, following the occurrence of a cardiac event. The findings add to the body of data supporting the use of tiotropium HandiHaler® in patients with COPD, irrespective of pre-existing cardiac conditions.