The cardiovascular risk of tiotropium: is it real?
BACKGROUND
Anticholinergic agents are of noteworthy value in the treatment of chronic obstructive pulmonary disease (COPD), but concerns have been raised about a possible association between their use and cardiovascular (CV) morbidity and mortality. In this review, we have examined whether and why an anticholinergic agent, and in particular tiotropium, might cause CV risks.


METHODS
We first examine the potential pharmacological mechanisms that justify the CV risk with an anticholinergic agent, and then the main clinical trials, observational (cohort or case-control) studies, descriptive reviews and meta-analyses that have looked at the CV risks associated with long-term tiotropium, which are available in MEDLINE, EMBASE and Cochrane Controlled Trials Register databases, using the following MeSH, full text and keyword terms: tiotropium bromide OR Spiriva AND COPD OR chronic obstructive pulmonary disease.


RESULTS
The almost absolute confidence that there is no real increased risk for death or CV morbidity during treatment with this inhaled anticholinergic agent in patients with COPD because of the results of a large 4-year trial and a robust and extensive analysis of > 19,000 patients participating in placebo-controlled tiotropium clinical trials. Nonetheless, because high-risk patients such as those with coronary artery disease, heart failure, cardiac arrhythmia, hypoxemia requiring daytime oxygen therapy and a creatinine > 2 mg/dl were excluded from Phase III clinical trials, it is impossible to exclude these patients from an increased risk of drug-related cardiac events in a real-world setting.


CONCLUSIONS
Despite the recently raised concerns about an excess risk of CV adverse events with inhaled short-acting anticholinergic agents, the risk:benefit ratio of tiotropium bromide appears still favorable, although it is not known whether high-risk patients are at an increased risk of drug-related CV events.
Cazzola
Mario
M
University of Rome Tor Vergata, Department of Internal Medicine, Unit of Respiratory Clinical Pharmacology, Rome, Italy. mario.cazzola@uniroma2.it
Calzetta
Luigino
L
Matera
Maria Gabriella
MG
D000280:Administration, Inhalation; D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000453:epidemiology; D016022:Case-Control Studies; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D015897:Comorbidity; D004198:Disease Susceptibility; D004285:Dogs; D006321:Heart / Q000187:drug effects; D006801:Humans; D015201:Meta-Analysis as Topic; D015337:Multicenter Studies as Topic; D010275:Parasympathetic Nervous System / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000453:epidemiology; D011976:Receptors, Muscarinic / Q000187:drug effects; D012306:Risk; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000069447:Tiotropium Bromide
D018680:Cholinergic Antagonists; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide