Cardiovascular safety of tiotropium in patients with COPD.
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: > or = 4 weeks, randomized, double-blind, parallel-group, placebo-controlled. Inclusion/exclusion criteria were similar, including spirometry-confirmed COPD, > or = 10 pack-year smoking, and age > or = 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 FEV(1) = 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.


CONCLUSIONS
Tiotropium was associated with a reduction in the risk of all-cause mortality, CV mortality, and CV events.
Celli
Bartolome
B
Carita-St. Elizabeth's Medical Center, Boston, MA, USA. bcelli@cchcs.org
Decramer
Marc
M
Leimer
Inge
I
Vogel
Ulrich
U
Kesten
Steven
S
Tashkin
Donald P
DP
D000280:Administration, Inhalation; D000368:Aged; D002318:Cardiovascular Diseases / Q000150:complications / Q000453:epidemiology*; D002423:Cause of Death; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D015994:Incidence; D008297:Male; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D012189:Retrospective Studies; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013147:Spirometry; D015996:Survival Rate; D000069447:Tiotropium Bromide; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
D018680:Cholinergic Antagonists; D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide