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

Disclosures

Respiratory Research. 2015;16(65) 

In This Article

Methods

Full details of the UPLIFT® methodology, including patient eligibility criteria, have been published previously.[9]

Study Design and Patients

UPLIFT® was a 4-year, randomised, double-blind, placebo-controlled, parallel-group trial involving patients with moderate to very severe COPD. All patients gave written informed consent. The study was approved by local ethical review boards in each center (see Additional file 1 http://www.respiratory-research.com/content/16/1/65/additional) and conducted in accordance with the Declaration of Helsinki.

Patients were excluded from UPLIFT® if they had a recent history (≤6 months) of MI, any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year or hospitalisation for heart failure (New York Heart Association Class III or IV) within the past year. Patients were randomised to 18 μg of tiotropium or a matching placebo once daily, delivered through the HandiHaler®.[9] All respiratory medications, except other inhaled anticholinergic drugs, were permitted during the trial.

After randomisation to treatment groups, clinic visits occurred at 1 and 3 months, then every 3 months throughout the 4-year study period. Reports of adverse events (AEs) were collected at each visit. An independent data and safety monitoring committee reviewed data throughout the trial.

Analysis of Outcomes in Patients Experiencing a Cardiac Event During the Study

Patients who were selected for the post-hoc analyses had to have experienced a cardiac event with onset during treatment, but following the first occurrence of the cardiac event, they did not withdraw from UPLIFT® (either due to the event or for another reason).

Three types of cardiac events were investigated: arrhythmia (defined as Standardised Medical Dictionary for Regulatory Activities [MedDRA] Query [SMQ] Cardiac arrhythmias sub-SMQ Cardiac arrhythmia terms), MI (defined as SMQ ischaemic heart disease sub-SMQ Myocardial Infarction [broad]) and cardiac failure (defined as SMQ Cardiac Failure [narrow]).

Outcomes in patients treated with tiotropium were compared with those receiving placebo. Evaluations included the time to onset of the initial cardiac AE and occurrence of SAEs, cardiac SAEs (using MedDRA version 16.0 definitions) and fatal AEs (FAEs) in the time after the initial cardiac AE.

For the vital status analysis, FAEs were counted if the death occurred ≥1 day following the first cardiac event of interest (arrhythmia, MI or cardiac failure) and within 1440 days of drug start. For the on-treatment analysis, events were counted if the event occurred ≥1 day following the first cardiac event of interest (arrhythmia, MI or cardiac failure) until cessation of treatment plus 30 days.

A composite endpoint of MACE was included in the analyses. This endpoint represents fatal events in the system organ class (SOC) cardiac disorders and SOC vascular disorders combined with MI (fatal and non-fatal), stroke (fatal and non-fatal) and the following preferred terms: sudden death, sudden cardiac death and cardiac death. For the composite endpoint of fatal MACE, non-fatal MI and non-fatal stroke were removed. As a sensitivity analysis, fatal MACE plus the preferred term 'death unknown' was also analysed.

Statistical Analysis

Descriptive statistical analysis only is presented.

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