Results
Cardiac and Mortality Outcomes for Patients With Cardiac Arrhythmia During the UPLIFT® Study
In the UPLIFT® trial, 5993 patients were randomly assigned, 2987 to receive tiotropium and 3006 to receive placebo. During the study, 400 patients experienced cardiac arrhythmia: 197 within the placebo arm, and 203 in the tiotropium treatment arm. Immediately following the first event, there were 26 discontinuations: 16 within the placebo arm, 10 in the tiotropium treatment arm. Kaplan-Meier analysis revealed a trend to later onset of the initial cardiac arrhythmia event in the tiotropium group (Figure 1A).
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Figure 1.
Kaplan-Meier analysis of time to onset of the first event. (A) Cardiac arrhythmia, (B) MI and (C) cardiac failure. Time to event is censored at Day 1440. MI, myocardial infarction, SMQ, Standardised Medical Dictionary for Regulatory Activities Query.
Mean treatment duration after the first cardiac arrhythmia event was 576.0 days (standard deviation [SD]: 454.3) for placebo and 518.8 days (SD: 438.0) for tiotropium patients. Among those patients who were administered placebo and who experienced a cardiac arrhythmia during the study, 60.2% (109/181) subsequently experienced an SAE and 20.4% (37/181) experienced a cardiac SAE. Similar percentages of patients experienced SAEs (53.9% [104/193]) and cardiac SAEs (22.8% [44/193]) in the tiotropium arm (Table 1).
For patients who experienced a cardiac arrhythmia, FAEs on-treatment affected 19.9% of patients receiving placebo and 14.5% of patients treated with tiotropium (Table 1). Vital status analysis was similar, with FAEs occurring slightly more frequently in those who had received placebo (21.0%) compared with tiotropium (17.6%) (Table 1).
Evaluation of events on-treatment by MACE endpoints did not suggest an increase in events with tiotropium compared with placebo for any of the measures (Table 1; Additional file 2 http://www.respiratory-research.com/content/16/1/65/additional also provides a categorical breakdown of the incidence of fatal MACE, fatal MACE [including death unknown] and MACE). For patients with a cardiac arrhythmia, the incidence of on-treatment MACE was 13.8% in the placebo arm compared with 7.8% in the tiotropium arm. Fatal on-treatment MACE affected 8.3% of patients receiving placebo and 5.2% of patients treated with tiotropium; the incidence of fatal on-treatment MACE including death unknown was 9.9% and 6.7%, respectively.
Cardiac and Mortality Outcomes for Patients With an MI During the UPLIFT® Study
During the study period, 172 patients experienced an MI: 92 within the placebo arm, 80 in the tiotropium arm. Following the first event, there were 41 discontinuations: 24 in the placebo arm, 17 in the tiotropium arm. Similar to results for cardiac arrhythmia, Kaplan-Meier analysis of patients with an MI revealed a trend to later onset of the first MI event in the tiotropium arm compared with the placebo arm (Figure 1B).
Mean treatment duration following the first MI event was 581.7 days (SD: 444.1) in the placebo arm and 580.6 days (SD: 427.6) in the tiotropium arm. Among those patients administered placebo who had experienced an MI during the study, 55.9% subsequently experienced an SAE and 27.9% experienced a cardiac SAE. In the tiotropium arm, 68.3% of patients subsequently experienced an SAE and 28.6% experienced a cardiac SAE (Table 1).
Vital status FAEs in patients who had experienced an MI occurred with similar frequency in both those who had received placebo (16.2%) or tiotropium (12.7%) (Table 1). On-treatment FAEs were experienced by 16.2% of patients in the placebo arm and by 9.5% of patients in the tiotropium arm (Table 1).
Evaluation of the events on treatment by MACE endpoints did not suggest an increase in events with tiotropium compared with placebo for any of the measures (Table 1; Additional file 2 http://www.respiratory-research.com/content/16/1/65/additional). For patients who had an MI, the incidence of MACE was 16.2% in the placebo arm compared with 9.5% in the tiotropium arm. Fatal MACE (and fatal MACE including death unknown) affected 7.4% of patients receiving placebo and 4.8% of patients treated with tiotropium.
Cardiac and Mortality Outcomes for Patients With Cardiac Failure During the UPLIFT® Study
During the study period, 397 patients experienced cardiac failure: 213 within the placebo arm, 184 in the tiotropium arm. Following the first event, there were 56 discontinuations: 27 in the placebo arm, 29 in the tiotropium arm. Kaplan-Meier analysis revealed a trend to later onset of the first cardiac failure event with tiotropium compared with placebo (Figure 1C).
Mean treatment duration following the first cardiac failure was 474.3 days (SD: 417.6) in the placebo arm and 447.0 days (SD: 399.4) in the tiotropium arm. Among those administered placebo who experienced cardiac failure during the study, 60.8% subsequently experienced an SAE and 23.7% experienced a cardiac SAE. In the tiotropium arm, 58.7% of patients subsequently experienced an SAE and 28.4% experienced a cardiac SAE (Table 1).
Following a cardiac failure event, vital status FAEs occurred with similar frequency in both those who had received placebo (22.0%) and those on tiotropium (21.9%) (Table 1). On-treatment FAEs were experienced by 16.7% of patients in the placebo arm and 19.4% of patients in the tiotropium arm (Table 1).
Evaluation of events on treatment by MACE endpoints did not suggest an increase in events with tiotropium compared with placebo (Table 1; Additional file 2 http://www.respiratory-research.com/content/16/1/65/additional). For patients experiencing cardiac failure, the incidence of MACE was 12.4% in the placebo arm compared with 10.3% in the tiotropium arm. Fatal MACE affected 7.0% of patients receiving placebo and 7.1% of patients treated with tiotropium; the incidence of fatal MACE, including death unknown, was 8.6% and 7.1%, respectively.