Chest
Volume 137, Issue 1, January 2010, Pages 20-30
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Original Research
COPD
Cardiovascular Safety of Tiotropium in Patients With COPD

https://doi.org/10.1378/chest.09-0011Get rights and content

Background

The clinical trial safety database for tiotropium has been augmented with a 4-year trial in patients with COPD, which provides an opportunity to better evaluate the cardiovascular (CV) profile of tiotropium.

Methods

Trials with the following criteria were considered: ≥ 4 weeks, randomized, double-blind, parallel-group, placebo-controlled. Inclusion/exclusion criteria were similar, including spirometry-confirmed COPD, ≥ 10 pack-year smoking, and age ≥ 40 years. Adverse events were collected throughout each trial using standardized case report forms. Incidence rates (IRs) were determined from the total number of patients with an event divided by total time at risk. Rate ratios (RRs) and 95% CI for tiotropium/placebo were calculated. IRs were determined for all-cause mortality and selected CV events, including a composite CV end point encompassing CV deaths, nonfatal myocardial infarction (MI), nonfatal stroke, and the terms sudden death, sudden cardiac death, and cardiac death.

Results

There were 19,545 patients randomized: 10,846 (tiotropium) and 8,699 (placebo) from 30 trials. Mean FEV1 = 1.15 ± 0.46 L (41 ± 14% predicted), 76% men, mean age = 65 ± 9 years. Cumulative exposure to study drug was 13,146 (tiotropium) and 11,095 (placebo) patient-years. For all-cause mortality, the IR was 3.44 (tiotropium) and 4.10 (placebo) per 100 patient-years (RR [95% CI] = 0.88 [0.77–0.999]). IR for the CV end point was 2.15 (tiotropium) and 2.67 (placebo) per 100 patient-years (RR [95% CI] = 0.83 (0.71–0.98]). The IR for the CV mortality excluding nonfatal MI and stroke was 0.91 (tiotropium) and 1.24 (placebo) per 100 patient-years (RR [95% CI] = 0.77 [0.60–0.98]). For total MI, cardiac failure, and stroke the RRs (95% CI) were 0.78 (0.59–1.02), 0.82 (0.69–0.98), and 1.03 (0.79–1.35), respectively.

Conclusion

Tiotropium was associated with a reduction in the risk of all-cause mortality, CV mortality, and CV events.

Section snippets

Study Population

The pooled safety database consisted of 30 completed clinical trials as of September 2008 in the tiotropium (Boehringer Ingelheim GmbH; Ingelheim, Germany) project database. For inclusion, all trials used a placebo-controlled, double-blind, and parallel-group study design. Trials were restricted to COPD and of at least 4 weeks' duration. In order to be comprehensive, studies with the dry powder (capsules delivered via the HandiHaler) and soft mist (Respimat) formulations have been included.

The

Study Population

There were 19,545 patients randomized with 8,699 receiving placebo and 10,846 receiving tiotropium. Cumulative exposure to study drug (patient-years) was 13,146 for tiotropium and 11,095 for placebo. Baseline demographics (Table 2) were balanced between treatment groups. The mean age of the population was 65 ± 9 years and 76% were men. Mean baseline FEV1 was 1.15 ± 0.46 L (41 ± 14% predicted), FVC was 2.49 ± 0.82 L (70 ± 19% predicted), and FEV1/FVC was 0.47 ± 0.12. Thirty-four percent of

Discussion

The tiotropium clinical trial program described in this report represents a substantial database of 19,545 patients studied in randomized, double-blind, parallel-group, placebo-controlled trials for up to 4 years. The data set demonstrates reductions in overall adverse events, serious adverse events, and all-cause mortality. Similarly, reductions were observed for CV end points, including a composite CV-mortality end point. In addition, relative to the control group, the clinical trials have

Pooled Terms and the Associated Preferred Terms in Parenthesis Used in the Analyses

  • Aneurysm (aneurysm, aneurysm arteriovenous, aneurysm ruptured, aortic aneurysm, aortic aneurysm rupture, aortic aneurysm syphilitic, aortic dissection, aortic dissection rupture, aortic intramural hematoma, artery dissection, cardiac aneurysm, carotid aneurysm rupture, cerebral aneurysm ruptured syphilitic, Charcot-Bouchard microaneurysms, coronary artery aneurysm, coronary artery dissection, dissecting coronary artery aneurysm, femoral artery aneurysm, femoral artery dissection,

Acknowledgments

Author contributions: Dr Celli: contributed to the planning and data analysis and was the primary writer of the manuscript.

Dr Decramer: contributed to the planning, data analysis, and writing of the manuscript.

Dr Leimer: contributed to the collection and analysis of the data as a member of the Boehringer Ingelheim staff.

Dr Vogel: contributed to the collection and analysis of the data as a member of the Boehringer Ingelheim staff.

Dr Kesten: contributed to the access to the data, its analysis and

References (0)

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Funding/support: This study was funded by Boehringer Ingelheim and Pfizer.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

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