A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD.

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Abstract

The long-term use of inhaled anticholinergic agents has recently been suggested to be associated with an excess risk of adverse cardiovascular (CV) outcomes in patients with COPD. We identified 15 published studies that reported on the association between long-term inhaled anticholinergic use and adverse CV outcomes. Only 3 of the studies were adequately designed randomized controlled trials (RCTs). The first RCT that suggested that anticholinergic agents increased the risk of adverse CV outcomes was the Lung Health Study (LHS). Smokers randomized to inhaled ipratropium had a significantly increased risk of CV death than smokers receiving placebo. The LHS results have been questioned as the statistical tests used in the study were not adjusted for multiple tests and endpoints, a convincing dose-effect relationship between ipratropium use and the adverse CV outcomes was not established, and most of the CV deaths in the ipratropium group occurred in patients who were non-compliant to ipratropium. The Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) was a RCT that compared the combination of salmeterol plus fluticasone against tiotropium in patients with COPD. All-cause mortality was significantly lower in the salmeterol plus fluticasone group (3%) compared to the tiotropium group (6%). Fatal CV events occurred in 1% of the salmeterol plus fluticasone group compared to 3% in the tiotropium group. The INSPIRE trial was not designed to be a mortality trial, lacked adequate adjudication of fatal outcomes, and lacked a full intention-to-treat analysis of the data. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was a RCT comparing tiotropium and placebo in patients with COPD. Follow-up in UPLIFT was planned for 1440 days (4 years) plus 30 days (1470 days) of post-treatment follow-up. At 1440 days with 95% of patient outcome accounted for, tiotropium was associated with a significant 13% reduction in all-cause mortality compared to placebo. However, at 1470 days with only 75% of patient outcome accounted for, tiotropium was associated with a non-significant 11% reduction in all-cause mortality compared to placebo. The relative risks for serious CV events, heart failure, and myocardial infarction were all significantly lower with tiotropium than placebo. It is not certain why such a wide disparity in findings exists among the published studies evaluating the CV risks of inhaled anticholinergic agents. Prospective, adequately powered RCTs are needed to provide more evidence for the CV safety of tiotropium.

Original languageEnglish
Pages (from-to)253-263
Number of pages11
JournalInternational Journal of COPD
Volume4
StatePublished - 2009

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Cholinergic Antagonists
Chronic Obstructive Pulmonary Disease
Ipratropium
Randomized Controlled Trials
Placebos
Mortality
Tiotropium Bromide
Lung
Intention to Treat Analysis
Fatal Outcome
Health
Heart Failure
Myocardial Infarction
Safety

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

@article{b9fbf04ed4004cb380c7af33d82308bf,
title = "A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD.",
abstract = "The long-term use of inhaled anticholinergic agents has recently been suggested to be associated with an excess risk of adverse cardiovascular (CV) outcomes in patients with COPD. We identified 15 published studies that reported on the association between long-term inhaled anticholinergic use and adverse CV outcomes. Only 3 of the studies were adequately designed randomized controlled trials (RCTs). The first RCT that suggested that anticholinergic agents increased the risk of adverse CV outcomes was the Lung Health Study (LHS). Smokers randomized to inhaled ipratropium had a significantly increased risk of CV death than smokers receiving placebo. The LHS results have been questioned as the statistical tests used in the study were not adjusted for multiple tests and endpoints, a convincing dose-effect relationship between ipratropium use and the adverse CV outcomes was not established, and most of the CV deaths in the ipratropium group occurred in patients who were non-compliant to ipratropium. The Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) was a RCT that compared the combination of salmeterol plus fluticasone against tiotropium in patients with COPD. All-cause mortality was significantly lower in the salmeterol plus fluticasone group (3{\%}) compared to the tiotropium group (6{\%}). Fatal CV events occurred in 1{\%} of the salmeterol plus fluticasone group compared to 3{\%} in the tiotropium group. The INSPIRE trial was not designed to be a mortality trial, lacked adequate adjudication of fatal outcomes, and lacked a full intention-to-treat analysis of the data. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was a RCT comparing tiotropium and placebo in patients with COPD. Follow-up in UPLIFT was planned for 1440 days (4 years) plus 30 days (1470 days) of post-treatment follow-up. At 1440 days with 95{\%} of patient outcome accounted for, tiotropium was associated with a significant 13{\%} reduction in all-cause mortality compared to placebo. However, at 1470 days with only 75{\%} of patient outcome accounted for, tiotropium was associated with a non-significant 11{\%} reduction in all-cause mortality compared to placebo. The relative risks for serious CV events, heart failure, and myocardial infarction were all significantly lower with tiotropium than placebo. It is not certain why such a wide disparity in findings exists among the published studies evaluating the CV risks of inhaled anticholinergic agents. Prospective, adequately powered RCTs are needed to provide more evidence for the CV safety of tiotropium.",
author = "Hilleman, {Daniel E.} and Malesker, {Mark A.} and Morrow, {Lee E.} and Dan Schuller",
year = "2009",
language = "English",
volume = "4",
pages = "253--263",
journal = "International Journal of COPD",
issn = "1176-9106",
publisher = "Dove Medical Press Ltd.",

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T1 - A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD.

AU - Hilleman, Daniel E.

AU - Malesker, Mark A.

AU - Morrow, Lee E.

AU - Schuller, Dan

PY - 2009

Y1 - 2009

N2 - The long-term use of inhaled anticholinergic agents has recently been suggested to be associated with an excess risk of adverse cardiovascular (CV) outcomes in patients with COPD. We identified 15 published studies that reported on the association between long-term inhaled anticholinergic use and adverse CV outcomes. Only 3 of the studies were adequately designed randomized controlled trials (RCTs). The first RCT that suggested that anticholinergic agents increased the risk of adverse CV outcomes was the Lung Health Study (LHS). Smokers randomized to inhaled ipratropium had a significantly increased risk of CV death than smokers receiving placebo. The LHS results have been questioned as the statistical tests used in the study were not adjusted for multiple tests and endpoints, a convincing dose-effect relationship between ipratropium use and the adverse CV outcomes was not established, and most of the CV deaths in the ipratropium group occurred in patients who were non-compliant to ipratropium. The Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) was a RCT that compared the combination of salmeterol plus fluticasone against tiotropium in patients with COPD. All-cause mortality was significantly lower in the salmeterol plus fluticasone group (3%) compared to the tiotropium group (6%). Fatal CV events occurred in 1% of the salmeterol plus fluticasone group compared to 3% in the tiotropium group. The INSPIRE trial was not designed to be a mortality trial, lacked adequate adjudication of fatal outcomes, and lacked a full intention-to-treat analysis of the data. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was a RCT comparing tiotropium and placebo in patients with COPD. Follow-up in UPLIFT was planned for 1440 days (4 years) plus 30 days (1470 days) of post-treatment follow-up. At 1440 days with 95% of patient outcome accounted for, tiotropium was associated with a significant 13% reduction in all-cause mortality compared to placebo. However, at 1470 days with only 75% of patient outcome accounted for, tiotropium was associated with a non-significant 11% reduction in all-cause mortality compared to placebo. The relative risks for serious CV events, heart failure, and myocardial infarction were all significantly lower with tiotropium than placebo. It is not certain why such a wide disparity in findings exists among the published studies evaluating the CV risks of inhaled anticholinergic agents. Prospective, adequately powered RCTs are needed to provide more evidence for the CV safety of tiotropium.

AB - The long-term use of inhaled anticholinergic agents has recently been suggested to be associated with an excess risk of adverse cardiovascular (CV) outcomes in patients with COPD. We identified 15 published studies that reported on the association between long-term inhaled anticholinergic use and adverse CV outcomes. Only 3 of the studies were adequately designed randomized controlled trials (RCTs). The first RCT that suggested that anticholinergic agents increased the risk of adverse CV outcomes was the Lung Health Study (LHS). Smokers randomized to inhaled ipratropium had a significantly increased risk of CV death than smokers receiving placebo. The LHS results have been questioned as the statistical tests used in the study were not adjusted for multiple tests and endpoints, a convincing dose-effect relationship between ipratropium use and the adverse CV outcomes was not established, and most of the CV deaths in the ipratropium group occurred in patients who were non-compliant to ipratropium. The Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) was a RCT that compared the combination of salmeterol plus fluticasone against tiotropium in patients with COPD. All-cause mortality was significantly lower in the salmeterol plus fluticasone group (3%) compared to the tiotropium group (6%). Fatal CV events occurred in 1% of the salmeterol plus fluticasone group compared to 3% in the tiotropium group. The INSPIRE trial was not designed to be a mortality trial, lacked adequate adjudication of fatal outcomes, and lacked a full intention-to-treat analysis of the data. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was a RCT comparing tiotropium and placebo in patients with COPD. Follow-up in UPLIFT was planned for 1440 days (4 years) plus 30 days (1470 days) of post-treatment follow-up. At 1440 days with 95% of patient outcome accounted for, tiotropium was associated with a significant 13% reduction in all-cause mortality compared to placebo. However, at 1470 days with only 75% of patient outcome accounted for, tiotropium was associated with a non-significant 11% reduction in all-cause mortality compared to placebo. The relative risks for serious CV events, heart failure, and myocardial infarction were all significantly lower with tiotropium than placebo. It is not certain why such a wide disparity in findings exists among the published studies evaluating the CV risks of inhaled anticholinergic agents. Prospective, adequately powered RCTs are needed to provide more evidence for the CV safety of tiotropium.

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M3 - Review article

VL - 4

SP - 253

EP - 263

JO - International Journal of COPD

JF - International Journal of COPD

SN - 1176-9106

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