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Review | Clinician's Corner

Inhaled Anticholinergics and Risk of Major Adverse Cardiovascular Events in Patients With Chronic Obstructive Pulmonary Disease:  A Systematic Review and Meta-analysis FREE

Sonal Singh, MD, MPH; Yoon K. Loke, MBBS, MD; Curt D. Furberg, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Medicine (Dr Singh) and Division of Public Health Sciences (Dr Furberg), Wake Forest University School of Medicine, Winston-Salem, North Carolina; and School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, England (Dr Loke).


JAMA. 2008;300(12):1439-1450. doi:10.1001/jama.300.12.1439.
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Context Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown.

Objective To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke.

Data Sources Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers' trial registries with no date restrictions.

Study Selection Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events.

Data Extraction The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I2 statistic.

Data Synthesis After a detailed screening of 103 articles, 17 trials enrolling 14 783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7311 patients (1.2%) receiving control therapy (RR, 1.58 [95% confidence interval {CI}, 1.21-2.06]; P < .001, I2 = 0%). Among individual components of the primary end point, inhaled anticholinergics significantly increased the risk of MI (RR, 1.53 [95% CI 1.05-2.23]; P = .03, I2 = 0%) and cardiovascular death (RR, 1.80 [95% CI, 1.17-2.77]; P = .008, I2 = 0%) without a statistically significant increase in the risk of stroke (RR, 1.46 [95% CI, 0.81-2.62]; P = .20, I2 = 0%). All-cause mortality was reported in 149 of the patients treated with inhaled anticholinergics (2.0%) and 115 of the control patients (1.6%) (RR, 1.26 [95% CI, 0.99-1.61]; P = .06, I2 = 2%). A sensitivity analysis restricted to 5 long-term trials (>6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95%CI, 1.27-2.36]; P < .001, I2 = 0%).

Conclusion Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

Figures in this Article

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide.1,2 Inhaled anticholinergics include the short-acting muscarinic agonist ipratropium bromide, and the M1 and M3 selective long-acting muscarinic agonist tiotropium bromide. Inhaled tiotropium is the most widely prescribed agent for COPD.3 More than 8 million patients worldwide have used inhaled tiotropium since its approval in 2002,3 with net sales of €1792 million (approximately US $2.4 billion) in 2007.3

According to the recent COPD Global Initiative for Lung Disease guidelines, inhaled tiotropium is indicated for the long-term, once daily maintenance treatment of bronchospasm associated with COPD.1 The quaternary ammonium structure of inhaled anticholinergic agents limits their systemic bioavailability, and the only commonly recognized adverse effects include the development of anticholinergic effects, such as dry mouth and urinary retention.1

Cardiovascular disease is an important cause of morbidity and mortality in COPD. According to the recent COPD Global Initiative for Lung Disease guidelines: “an unexpected small increase in cardiovascular adverse events was noted with inhaled ipratropium bromide which deserves further investigation.”1,4 A pooled analysis of 19 short-term placebo-controlled trials revealed no significant increase in the risk of cardiovascular adverse events with inhaled tiotropium bromide in 2006.5 However, in an early communication in 2008, the US Food and Drug Administration reported that patients in the inhaled tiotropium group experienced a “possible increased risk of stroke” based on a pooled analysis of 29 trials involving 13 500 patients with COPD.6 The risk of stroke was 8/1000 per year in the tiotropium group compared with 6/1000 per year in the placebo group.

It is important to establish the complete cardiovascular safety profile of inhaled anticholinergics in patients with COPD due to the widespread use of these agents. Our primary objective was to systematically ascertain the cardiovascular risks (myocardial infarction [MI], stroke, and cardiovascular death) associated with the long-term use of inhaled anticholinergics (ipratropium bromide and tiotropium bromide) compared with control therapies in patients with COPD in randomized controlled trials (RCTs).

Eligibility Criteria

Our specific inclusion criteria for trials were (1) study design consisting of an RCT for any inhaled anticholinergic (ipratropium bromide or tiotropium bromide) with more than 30 days of follow-up; (2) study participants with a diagnosis of COPD of any severity; (3) an inhaled anticholinergic as the intervention drug vs a control, which could be placebo or active control (eg, inhaled β-agonists or inhaled steroid β-agonist combinations); and (4) the trial had to report data on the incidence of serious cardiovascular adverse events, including MI, stroke, or cardiovascular death. All RCTs that recruited patients with asthma were excluded.

Search Strategy

On March 19, 2008, 2 reviewers (S.S. and Y.K.L.) independently and in duplicate searched MEDLINE through PubMed with the clinical trial filter using the search terms ipratropium and tiotropium and chronic and obstructive with no date restrictions. In addition, trials were retrieved from the Cochrane Database of systematic reviews, Web sites of the US Food and Drug Administration and European regulatory authorities, clinical trials.gov, and manufacturers' product information sheets. Trial reports also were evaluated of all published or unpublished trials with inhaled ipratropium bromide and tiotropium bromide in the clinical trials register of the manufacturers.7 We searched the included and excluded trials' lists from systematic reviews and meta-analysis of inhaled anticholinergics in COPD,5,812 checked for relevant data on adverse events within these systematic reviews, searched the bibliographies of included studies, and used the Web of Science Citation Index to identify relevant cited and citing articles. Our search was limited to English-language articles and included unpublished studies.

Study Selection

Two reviewers (S.S. and Y.K.L.) independently and in duplicate scanned all titles and abstracts that indicated whether a study was an RCT evaluating inhaled anticholinergics in patients with COPD. After obtaining full reports of potentially relevant trials, the same reviewers independently assessed eligibility from full-text articles. Disagreements regarding eligibility were resolved with a third reviewer (C.D.F.) through consensus.

Study Characteristics

A standard protocol was used to record the following properties of each study: the dose and frequency of the inhaled anticholinergic and control interventions, location and duration of the study (in weeks), primary outcome, mean age and sex of participants, percentage of current smokers enrolled, severity of COPD in the participants as mean predicted forced expiratory volume in the first second of expiration (FEV1), and proportion of participants with preexisting cardiac disease or cardiovascular risk factors if available.

Validity Assessment

Two reviewers (S.S. and Y.K.L.) independently and in duplicate assessed each included study for the reporting of allocation concealment, the use of blinding, loss to follow-up, and withdrawal rates. To determine the strength of adverse event monitoring, the frequency and type of adverse event monitoring during the follow-up period were evaluated based on the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions on assessing adverse effects.13

Outcome Measures

The primary outcome measure was prespecified as a composite of nonfatal MI, nonfatal stroke (including transient ischemic attack), and cardiovascular death (including sudden death). These major adverse cardiovascular events represent serious ischemic events and are a widely used end point in cardiovascular outcome trials.14 Because none of the trials were prospectively designed to assess the cardiovascular risk of inhaled anticholinergics in patients with COPD, cardiovascular end points may not have been prospectively defined in a uniform fashion across the trials but were ascertained through routine serious adverse event reporting within each trial. The risk of all-cause mortality also was determined in the included trials as a secondary outcome.

Data Extraction

Two reviewers (S.S. and Y.K.L.) independently and separately extracted data (including 0 events) on MI, stroke, cardiovascular death, and all-cause mortality among trial listings of serious adverse events; a third reviewer (C.D.F.) adjudicated in the event of discrepancies. Data in the clinical trials register and the regulatory documents were reconciled with that of the published journal article when possible. If there were multiple reports for a particular study, data from the most recent version were extracted. When specific aspects of the data required clarification, the authors of the original articles were contacted.

Quantitative Data Synthesis and Sensitivity Analysis

Review Manager (RevMan) version 5.04 (Nordic Cochrane Center, Copenhagen, Denmark) was used to calculate relative risk (RR) and 95% confidence intervals (CIs) for the primary composite outcome (cardiovascular death, MI, and stroke), the individual end points of the composite, as well as all-cause mortality. All reported P values are 2-sided with significance set at less than .05. Statistical heterogeneity was assessed using the I2 statistic.15 I2 values of 50% or more indicate a substantial level of heterogeneity. We planned to pool data across studies using the fixed-effects models if substantial statistical heterogeneity was not present.

A predefined sensitivity analysis was performed to explore the influence on the effect size for statistical models (fixed and random effects), trial duration, and completeness in reporting of individual end points of the primary outcome, and the influence of the individual studies. The fail-safe number, using the Rosenberg method,16 was calculated to evaluate the potential impact of unpublished studies on the meta-analysis. The fail-safe number indicates the number of nonsignificant unpublished studies that would need to be added to a meta-analysis to reverse an overall statistically significant result to nonsignificance.16

The number needed to harm (NNH) (and 95% CI) with inhaled anticholinergics was calculated by applying the RR estimates to the cardiovascular event rate in a large population-based study using Visual Rx, version 2.0.17 The NNH varies when inhaled anticholinergics are used in a general population outside highly selected trial participants.18Quiz Ref IDThe NNH is the number of patients with COPD who need to be treated with inhaled anticholinergics rather than with placebo or comparators for 1 additional patient to be harmed by a cardiovascular adverse event.

Of the 703 potentially relevant citations identified, 17 trials fulfilled the inclusion criteria after a detailed review of 103 studies.4,1934 The flow of the trial is shown in Figure 1. Trial characteristics are shown in Table 1.

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Figure 1. Study Selection
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Table Graphic Jump LocationTable 1. Characteristics of Randomized Controlled Trials of Inhaled Anticholinergics Included in the Analysis of Major Adverse Cardiovascular Events

The trials included 14 783 participants, in which 7472 received inhaled anticholinergics and 7311 received control therapy. Twelve trials evaluated inhaled tiotropium vs control therapy,1930 and 5 trials evaluated inhaled ipratropium vs control therapy.4,3134 Nine trials evaluated inhaled anticholinergics vs placebo.4,19,2123,26,27,29,30 The remaining trials used active comparators, including inhaled salmeterol,24,25,3234 a combination inhaler containing salmeterol and fluticasone,20,28 or inhaled albuterol.31 There were 5 long-term trials ranging from 48 weeks to 5 years,4,1922 and 12 short-term trials ranging from 6 weeks to 26 weeks.2334 The mean predicted FEV1 of participants was less than 50% for all trials, except 1 trial4 in which the mean predicted FEV1 was 75%.

The quality assessment of included trials is shown in Table 2. Trial quality was variable. All trials were double-blinded. Allocation concealment was adequate in 4 RCTs,4,20,23,27 and unclear in the remaining 13 RCTs.19,21,22,2426,2834 Information on withdrawal rates was available for all RCTs except 1 trial,28 and ranged from 6.1%23 to as high as 42%.20 Reporting of loss to follow-up was variable and only available for 6 RCTs4,20,27,29,31,34 and ranged from 0%34 to 3.4%.29

Table Graphic Jump LocationTable 2. Quality Assessment of Included Trials

Data on MI, stroke, cardiovascular death, the major adverse cardiovascular event composite, and all-cause mortality are shown in Table 3.

Table Graphic Jump LocationTable 3. Cardiovascular Events and All-Cause Mortality in Randomized Controlled Trials of Inhaled Anticholinergics
Primary Outcome

Inhaled anticholinergics significantly increased the risk of cardiovascular death, MI, or stroke (1.8% vs 1.2% for control; RR,1.58 [95% CI, 1.21-2.06]; P < .001)in a meta-analysis of 17 trials involving 14 783 patients (Figure 2).4,1934 There was no evidence of statistical heterogeneity among the included trials (I2 = 0%).

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Figure 2. Meta-analysis of Randomized Controlled Trials of Inhaled Anticholinergics vs Control for Major Adverse Cardiovascular Outcomes Composite
Graphic Jump Location

Cardiovascular outcomes composite indicates cardiovascular death, myocardial infarction, and stroke. Size of the data markers indicates weight of the study. CI indicates confidence interval.

Quiz Ref IDAmong individual components of the primary outcome, inhaled anticholinergics significantly increased the risk of MI (1.2% vs 0.8% for control; RR, 1.53 [95% CI, 1.05-2.23]; P = .03) in a meta-analysis of 11 trials involving 10 598 patients.4,1922,24,26,28,3133 Inhaled anticholinergics also significantly increased the risk of cardiovascular death (0.9% vs 0.5% for control; RR, 1.80 [95% CI, 1.17-2.77]; P = .008) in a meta-analysis of 12 trials involving 12 376 patients.4,1921,2325,27,2931,33 Inhaled anticholinergics did not significantly increase the risk of stroke (0.5% vs 0.4% for control; RR, 1.46 [95% CI, 0.81-2.62]; P = .20) in a meta-analysis of 7 trials involving 9251 patients.4,19,20,24,3234 There was no evidence of statistical heterogeneity among the included trials for any of these end points (I2 = 0% for MI, cardiovascular death, and stroke) (Table 4).

Table Graphic Jump LocationTable 4. Results of Meta-Analysis on Individual End Points of Cardiovascular Death, Myocardial Infarction (MI), Stroke, and All-Cause Mortality With Inhaled Anticholinergics
Secondary Outcome

Inhaled anticholinergics did not significantly increase the risk of all-cause mortality (2.0% vs 1.6% for control; RR, 1.26 [95%CI, 0.99-1.61]; P = .06) in a meta-analysis of 17 trials involving 14 783 patients.4,1934 There was evidence of low statistical heterogeneity among the included trials (I2 = 2%) (Table 4).

Sensitivity Analysis

The random-effects analysis of the primary composite outcome of cardiovascular death, MI, and stroke from the 17 trials4,1934 yielded effect sizes (RR, 1.57 [95% CI, 1.19-2.06]; P = .001) similar in magnitude and direction to those obtained from the fixed-effects analysis.

Inhaled anticholinergics significantly increased the risk of cardiovascular death, MI, and stroke in a sensitivity analysis limited to the 5 long-term trials (>6 months) involving 7267 patients (2.9% vs 1.8% for control; RR, 1.73 [95% CI, 1.27-2.36]; P < .001) (Figure 3).4,1922 There was no evidence of statistical heterogeneity among the trials (I2 = 0%).4,1922 The significantly increased risk of cardiovascular death, MI, and stroke was demonstrated even when we separately analyzed inhaled tiotropium vs control therapy (RR, 2.12 [95% CI, 1.22-3.67]; P = .008),1922 and inhaled ipratropium vs control therapy (RR, 1.57 [95% CI, 1.08-2.28]; P = .02)4 in the long-term trials. Although, there was no statistically significant increase in the risk of cardiovascular death, MI, and stroke in a sensitivity analysis of the 12 short-term trials (<26 weeks) involving 7516 patients (0.6% for anticholinergics vs 0.6% for control; RR, 1.16 [95% CI, 0.67-2.01]; P = .60),the direction of the drug effect was similar to that of the long-term trials (Figure 4).2334 There was no evidence of statistical heterogeneity among the trials (I2 = 0%).

Place holder to copy figure label and caption
Figure 3. Meta-analysis of Long-Term Randomized Controlled Trials of Inhaled Anticholinergics vs Control for Major Adverse Cardiovascular Outcomes Composite
Graphic Jump Location

Cardiovascular outcomes composite indicates cardiovascular death, myocardial infarction, and stroke. Long-term indicates longer than 6 months to 5 years. Size of the data markers indicates weight of the study. CI indicates confidence interval.

Place holder to copy figure label and caption
Figure 4. Meta-analysis of Short-Term Randomized Controlled Trials of Inhaled Anticholinergics vs Control for Major Adverse Cardiovascular Outcomes Composite
Graphic Jump Location

Cardiovascular outcomes composite indicates cardiovascular death, myocardial infarction, and stroke. Short-term indicates 6 weeks to 6 months. Size of the data markers indicates weight of the study. CI indicates confidence interval.

After excluding 5 trials for which data on some individual end points of the composite were unavailable,22,23,25,27,31 the sensitivity analysis limited to 12 trials, which provided complete reporting on individual end points of the primary composite outcome of cardiovascular death, MI, and stroke,4,1921,24,26,2830,3234 yielded effect sizes (RR, 1.63 [95% CI, 1.22-2.16]; P < .001) similar in magnitude and direction to those obtained from 17 trials.

After excluding the trial that contributed to more than 50% of the weight in the fixed-effects model (and the largest sample size and longest duration of follow-up),4 the sensitivity analysis limited to the remaining 16 trials on the primary composite outcome of cardiovascular death, MI, and stroke1934 yielded effect sizes (RR, 1.58 [95% CI, 1.08-2.33]; P = .02) similar in magnitude and direction to those obtained from the 17 trials. There was no evidence of statistical heterogeneity among the trials (I2 = 0%).

Fail-Safe Number

According to Rosenberg method, 16 nonsignificant long-term trials of inhaled anticholinergics each with a sample size of approximately 1450 participants (the mean sample size of the 5 long-term trials) would be required to reverse the significantly increased risk of cardiovascular death, MI, and stroke seen with long-term inhaled anticholinergic use in the 5 long-term trials.4,1922

Estimated NNH With Inhaled Anticholinergics for MI and Cardiovascular Death

Assuming a baseline MI event rate of 10.9/1000 person-years in adult patients with COPD from a population-based observational study (nearly 54% male and 75% >65 years),35 the NNH for MI with inhaled anticholinergics is estimated to be approximately 174 per year (95% CI, 75-1835 per year). Assuming a baseline cardiovascular mortality event rate of 31.9/1000 person-years in adult patients with COPD from a population-based observational study,35 the NNH for cardiovascular death with inhaled anticholinergics is estimated to be approximately 40 per year (95% CI, 18-185 per year).

Inhaled anticholinergic use for more than 30 days significantly increases the risk of cardiovascular death, MI, or stroke in patients with COPD by approximately 58%. This increase in the risk of cardiovascular death, MI, or stroke is particularly manifest in the long-term trials. However, in the short-term trials, inhaled anticholinergics do not significantly increase the risk of cardiovascular death, MI, or stroke, although the direction of the effect is similar to that of the long-term trials. Inhaled anticholinergics also significantly increase the risk of the individual end points of MI and cardiovascular death without a statistically significant increase in the risk of stroke and all-cause mortality.

The significant increase in the risk of cardiovascular death, MI, or stroke, without a significant increase in all-cause mortality with inhaled anticholinergics, may have 2 possible explanations—lack of statistical power to detect differences in all-cause mortality or an off-setting reduction of respiratory mortality with inhaled anticholinergics. It is more likely that the trials were inadequately powered to detect differences in all-cause mortality because inhaled anticholinergics have not been shown to reduce respiratory-related mortality in a clinical trial. The increased risk of cardiovascular death, MI, or stroke with inhaled anticholinergics cannot be attributed to the protective effects of comparators because neither inhaled β-agonists nor inhaled steroid and β-agonist combination inhaler reduce cardiovascular outcomes in patients with COPD. On the contrary, there are concerns about an excess risk of cardiovascular adverse events with β-agonists in patients with obstructive lung disease.36

Our findings need to be distinguished from other meta-analyses of short-term trials. We specifically evaluated the risk of cardiovascular death, MI, and stroke with both inhaled anticholinergic agents, restricted our analysis to patients with COPD, and incorporated unpublished data from several recently published long-term trials of inhaled tiotropium.1922 A meta-analysis of several short-term placebo-controlled trials reported that inhaled tiotropium use had no significant effect on the risk of MI (RR, 0.72 [95% CI, 0.26-2.07]), cardiovascular mortality (RR, 0.57 [95% CI, 0.26-1.26]), respiratory mortality (RR, 0.71 [95%CI, 0.29-1.74]), and all-cause mortality (RR, 0.76 [95% CI, 0.5-1.16]).5 Other meta-analyses also have failed to discern any effect of inhaled anticholinergics on all-cause mortality.810

The increased risk of cardiovascular death, stroke, or MI associated with inhaled anticholinergic use seen in our meta-analysis should be interpreted in the context of the evidence from recent population-based studies.3740 However, these database studies are susceptible to residual confounding, misclassification bias, and channeling bias. A nested case-control study among patients with COPD, using the Manitoba health database,reported an increased risk of hospitalization for MI (odds ratio [OR], 1.42 [95% CI, 1.24-1.63]), heart failure (OR, 3.07 [95% CI, 2.82-3.34]), and stroke (OR, 1.18 [95% CI, 1.04-1.33]) among those who had used inhaled ipratropium bromide 60 days prior to the event compared with controls.37 Another observational cohort study in the Veterans Affairs database reported that inhaled ipratropium exposure was associated with a nearly 34% significant increase in the risk of cardiovascular death (OR, 1.34 [95% CI, 1-22-1.47]) with an estimated annualized NNH at 261.38 Another industry-funded cohort study using the Health Information Network database in the United Kingdom among a broad population of users reported a nonsignificant higher risk of MI with inhaled tiotropium (hazard ratio, 1.29 [95% CI, 0.45-3.66]), without any difference in the risk of overall mortality (hazard ratio, 0.93 [95% CI, 0.59-1.44]), compared with long-acting β-agonists.39 Another industry-funded, population-based cohort study in Denmark among 10 603 predominantly elderly (75% = 60years) participants with COPD and a mean follow-up of 18 months, also reported a nonsignificant higher risk of hospitalization for MI with inhaled tiotropium users (RR, 1.25 [95% CI, 0.49-3.17]) with a significant reduction in overall mortality (RR, 0.77 [95% CI, 0.65-0.91]) compared with nonusers.40

Quiz Ref IDThe precise biological mechanisms by which inhaled anticholinergics increase the risk of cardiovascular death, MI, or stroke among patients with COPD are uncertain. In the Lung Health Study,4 there was an increase in the incidence of supraventricular tachycardia with inhaled ipratropium consistent with the vagolytic nature of the drug. Chronic obstructive pulmonary disease is increasingly being recognized as a systemic inflammatory disease and inflammatory cytokines may potentially play a role in mediating the systemic cardiovascular effects of COPD.41 Inhaled tiotropium significantly increased the risk of sputum IL-8 (P = .04) compared with placebo in a year-long placebo-controlled trial, without any significant difference in the levels of serum C-reactive protein and IL-6 levels.21 Serum IL-8 also may increase the risk of cardiovascular events by destabilizing existing atherosclerotic plaque.42 It needs to be investigated whether this increased risk of cardiovascular events is mediated via inflammatory cytokines.

Our study has limitations, which mainly stem from the quality of reported data. Many of these trials were small and short-term, resulting in few events. As a result of small numbers, the 95% CIs are wide, resulting in some uncertainty as to the precise magnitude of the observed risk. None of these trials were specifically designed to monitor the risk of cardiovascular events, which were not adjudicated. The reporting of cardiovascular outcomes may have been incomplete. The lack of availability of source data did not allow the use of more statistically powerful time-to-event analysis or assessment of dose-responsiveness or stratified analysis based on FEV1 (an independent predictor of cardiovascular death in COPD),43 current smoking, hypertension, diabetes, hypercholesterolemia, coronary artery disease, and the concomitant use of cardioprotective agents (statins, angiotensin-converting enzyme inhibitors).44 We did not have data to determine intraclass differences in the risk of cardiovascular events. A meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest.

Prospective, adequately powered trials with adjudication of cardiovascular events are needed to assess the cardiovascular safety of inhaled anticholinergics in patients with COPD. These trials should provide evidence on the comparative effectiveness and safety of the currently available long-acting bronchodilators. A randomized, double-blind, placebo-controlled, 4-year trial involving more than 6000 patients with COPD, the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) study, is evaluating the effect of tiotropium on the long-term decline in lung function and overall mortality in patients with COPD.45 However, this trial has not been specifically designed to address cardiovascular adverse events, and may not provide information on nonfatal cardiovascular adverse events, as well as the cardiovascular adverse effects of inhaled ipratropium. Sixteen negative long-term trials with an average sample size of 1450 participants would be required to render nonsignificant the results from our meta-analysis of long-term trials.

These risks of inhaled anticholinergics should be balanced against their benefits.Quiz Ref IDThe benefits of inhaled anticholinergics, such as tiotropium bromide, include symptomatic improvements seen in an increase in exercise capacity, reduction in the frequency of exacerbations (13%-25%),10 fewer hospitalizations because of exacerbations, improvements in dyspnea sensation as measured by the transition dyspnea index, and statistically significant improvement in health-related quality-of-life measures such as the St George Respiratory questionnaire.1Quiz Ref IDThe number needed to treat for tiotropium to prevent 1 COPD exacerbation is around 21 (95% CI,13-50),11 or COPD-related hospitalization is around 20 (95% CI, 14-34) compared with placebo.11 This should be weighed against the NNH of 40 for cardiovascular death and 174 for MI with inhaled anticholinergics in a typical US COPD population. Clinicians should evaluate the baseline cardiovascular risk status when considering inhaled anticholinergic therapy because patients with lower baseline cardiovascular risk will have higher and more favorable NNH for cardiovascular events associated with inhaled anticholinergics.

Unfortunately, alternative effective therapeutic options for patients with COPD are limited. The other long-acting bronchodilator, such as the inhaled β-agonist, and steroid combinations have similar efficacy,10 but a different adverse effect profile. An inhaled combination of salmeterol and fluticasone failed to significantly reduce mortality (HR, 0.83 [95% CI, 0.68-1.00]; P = .052) compared with placebo, but was associated with a significantly increased probability of pneumonia (19.6% vs 12.3%; P < .001) compared with placebo in the Toward a Revolution in COPD Health (TORCH) trial.46

Despite certain limitations, our findings have potential implications. Our findings indicate an increased risk of cardiovascular death, MI, or stroke with inhaled anticholinergic agents in patients with COPD. Chronic obstructive pulmonary disease is an independent risk factor for cardiovascular hospitalization and cardiovascular death.47 Cardiovascular death is a more frequent cause of death in patients with COPD than respiratory causes,48 with the proportion of cardiovascular deaths increasing with the severity of the disease.49 Clinicians need to closely monitor patients with COPD who are taking long-term anticholinergics for the development of cardiovascular events. Clinicians and patients should carefully consider these potential long-term cardiovascular risks of inhaled anticholinergics in the treatment of COPD, and decide whether these risks are an acceptable trade-off in return for their symptomatic benefits.

Corresponding Author: Sonal Singh, MD, MPH, Department of Medicine, One Medical Center Blvd, Wake Forest University School of Medicine, Winston-Salem, NC 27157 (sosingh@wfubmc.edu).

Author Contributions: Dr Singh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Singh, Loke.

Acquisition of data: Singh, Loke.

Analysis and interpretation of data: Singh, Loke, Furberg.

Drafting of the manuscript: Singh, Loke.

Critical revision of the manuscript for important intellectual content: Singh, Loke, Furberg.

Statistical analysis: Singh, Loke.

Administrative, technical, or material support: Singh.

Study supervision: Singh, Furberg.

Financial Disclosures: None reported.

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PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Rosenberg MS. The file-drawer problem revisited: a general weighted method for calculating fail-safe numbers in meta-analysis.  Evolution. 2005;59(2):464-468
PubMed
Dr Chris Cates' EBM Web site. http://www.nntonline.net. Accessed August 5, 2008
McQuay HJ, Moore RA. Using numerical results from systematic reviews in clinical practice.  Ann Intern Med. 1997;126(9):712-720
PubMed   |  Link to Article
Casaburi R, Mahler DA, Jones PW,  et al.  A long-term evaluation of once daily-inhaled tiotropium in chronic obstructive pulmonary disease.  Eur Respir J. 2002;19(2):217-224
PubMed   |  Link to Article
Wedzicha JA, Calverley PMA, Seemungal TA,  et al.  The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.  Am J Respir Crit Care Med. 2008;177(1):19-26
PubMed   |  Link to Article
Powrie DJ, Wilkinson TMA, Donaldson GC,  et al.  Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.  Eur Respir J. 2007;30(3):472-478
PubMed   |  Link to Article
Chan CK, Maltais F, Sigouin C, Haddon JM, Ford GT.SAFE Study Group.  A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease.  Can Respir J. 2007;14(8):465-472
PubMed
Casaburi R, Briggs DD Jr, Donohue JF, Serby CW, Menjoge SS, Witek TJ Jr.US Tiotropium Study Group.  The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial.  Chest. 2000;118(5):1294-1302
PubMed   |  Link to Article
Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD [published correction appears in Thorax. 2005;60(2):105].  Thorax. 2003;58(5):399-404
PubMed   |  Link to Article
Donohue JF, van Noord JA, Bateman ED,  et al.  A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.  Chest. 2002;122(1):47-55
PubMed   |  Link to Article
Covelli H, Bhattacharya S, Cassino C, Conoscenti C, Kesten S. Absence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary disease.  Pharmacotherapy. 2005;25(12):1708-1718
PubMed   |  Link to Article
Niewoehner DE, Rice K, Cote C,  et al.  Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.  Ann Intern Med. 2005;143(5):317-326
PubMed   |  Link to Article
Bateman ED, van Dyk M, Sagriotis A. Comparable spirometric efficacy of tiotropium compared with salmeterol plus fluticasone in patients with COPD: a pilot study.  Pulm Pharmacol Ther. 2008;21(1):20-25
PubMed   |  Link to Article
Moita J, Bárbara C, Cardoso J,  et al.  Tiotropium improves FEV1 in patients with COPD irrespective of smoking status [published ahead of print May 18, 2007].  Pulm Pharmacol Ther. 2008;21(1):146-151
PubMed   |  Link to Article
Voshaar T, Lapidus R, Maleki-Yazdi R,  et al.  A randomized study of tiotropium respimat® soft MistTM inhaler vs. ipratropium pMDI in COPD.  Respir Med. 2008;102(1):32-41
PubMed   |  Link to Article
Combivent Inhalation Aerosol Study Group.  In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial.  Chest. 1994;105(5):1411-1419
PubMed   |  Link to Article
GlaxoSmithKline.  Clinical trial register for a multicenter, randomized, double-blind, double-dummy, parallel group, 8-week comparison of salmeterol xinafoate versus ipratropium bromide versus salmeterol xinafoate plus ipratropium bromide versus placebo in subjects with chronic obstructive pulmonary disease. http://ctr.gsk.co.uk/Summary/salmeterol/IV_SMS40315.pdf. Accessed August 5, 2008
GlaxoSmithKline.  Clinical trial register for a multicenter, randomized, double-blind, double-dummy, parallel-group, 8-week comparison of salmeterol xinafoate versus ipratropium bromide versus salmeterol xinafoate plus ipratropium bromide versus placebo in subjects with chronic obstructive pulmonary disease. http://ctr.gsk.co.uk/Summary/salmeterol/IV_SMS40314.pdf. Accessed August 5, 2008
Mahler DA, Donohue JF, Barbee RA,  et al.  Efficacy of salmeterol xinafoate in the treatment of COPD.  Chest. 1999;115(4):957-965
PubMed   |  Link to Article
Curkendall SM, DeLuise C, Jones JK,  et al.  Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan, Canada, cardiovascular disease in COPD patients.  Ann Epidemiol. 2006;16(1):63-70
PubMed   |  Link to Article
Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis.  Chest. 2004;125(6):2309-2321
PubMed   |  Link to Article
Macie C, Wooldrage K, Manfreda J, Anthonisen N. Cardiovascular morbidity and the use of inhaled bronchodilators.  Int J Chron Obstruct Pulmon Dis. 2008;3(1):163-169
PubMed
Lee TA.US Department of Veterans Affairs.  Outcomes associated with salmeterol use in obstructive lung disease (September 2007). http://www.hsrd.research.va.gov/research/abstracts.cfm?Project_ID=2141694968&UnderReview=no. Accessed August 5, 2008
Jara M, Lanes SF, Wentworth C III, May C, Kesten S. Comparative safety of long-acting inhaled bronchodilators: a cohort study using the UK THIN primary care database.  Drug Saf. 2007;30(12):1151-1160
PubMed   |  Link to Article
de Luise C, Lanes SF, Jacobsen J, Pedersen L, Sørensen HT. Cardiovascular and respiratory hospitalizations and mortality among users of tiotropium in Denmark.  Eur J Epidemiol. 2007;22(4):267-272
PubMed   |  Link to Article
Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? the potential role of systemic inflammation in chronic obstructive pulmonary disease.  Circulation. 2003;107(11):1514-1519
PubMed   |  Link to Article
Boekholdt SM, Peters RJ, Hack CE,  et al.  IL-8 plasma concentrations and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study.  Arterioscler Thromb Vasc Biol. 2004;24(8):1503-1508
PubMed   |  Link to Article
Ebi-Kryston KL. Respiratory symptoms and pulmonary function as predictors of 10-year mortality from respiratory disease, cardiovascular disease, and all causes in the Whitehall Study.  J Clin Epidemiol. 1988;41(3):251-260
PubMed   |  Link to Article
Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease.  J Am Coll Cardiol. 2006;47(12):2554-2560
PubMed   |  Link to Article
Decramer M, Celli B, Tashkin DP,  et al.  Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: the UPLIFT trial.  COPD. 2004;1(2):303-312
PubMed   |  Link to Article
Calverley PMA, Anderson JA, Celli B,  et al.  Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.  N Engl J Med. 2007;356(8):775-789
PubMed   |  Link to Article
Sidney S, Sorel M, Quesenberry CP Jr,  et al.  COPD and incident cardiovascular disease hospitalizations and mortality: Kaiser Permanente medical care program.  Chest. 2005;128(4):2068-2075
PubMed   |  Link to Article
Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD.  Chest. 2005;128(4):2640-2646
PubMed   |  Link to Article
Mannino DM. Epidemiology and global impact of chronic obstructive pulmonary disease.  Semin Respir Crit Care Med. 2005;26(2):204-210
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Study Selection
Graphic Jump Location
Place holder to copy figure label and caption
Figure 2. Meta-analysis of Randomized Controlled Trials of Inhaled Anticholinergics vs Control for Major Adverse Cardiovascular Outcomes Composite
Graphic Jump Location

Cardiovascular outcomes composite indicates cardiovascular death, myocardial infarction, and stroke. Size of the data markers indicates weight of the study. CI indicates confidence interval.

Place holder to copy figure label and caption
Figure 3. Meta-analysis of Long-Term Randomized Controlled Trials of Inhaled Anticholinergics vs Control for Major Adverse Cardiovascular Outcomes Composite
Graphic Jump Location

Cardiovascular outcomes composite indicates cardiovascular death, myocardial infarction, and stroke. Long-term indicates longer than 6 months to 5 years. Size of the data markers indicates weight of the study. CI indicates confidence interval.

Place holder to copy figure label and caption
Figure 4. Meta-analysis of Short-Term Randomized Controlled Trials of Inhaled Anticholinergics vs Control for Major Adverse Cardiovascular Outcomes Composite
Graphic Jump Location

Cardiovascular outcomes composite indicates cardiovascular death, myocardial infarction, and stroke. Short-term indicates 6 weeks to 6 months. Size of the data markers indicates weight of the study. CI indicates confidence interval.

Tables

Table Graphic Jump LocationTable 1. Characteristics of Randomized Controlled Trials of Inhaled Anticholinergics Included in the Analysis of Major Adverse Cardiovascular Events
Table Graphic Jump LocationTable 2. Quality Assessment of Included Trials
Table Graphic Jump LocationTable 3. Cardiovascular Events and All-Cause Mortality in Randomized Controlled Trials of Inhaled Anticholinergics
Table Graphic Jump LocationTable 4. Results of Meta-Analysis on Individual End Points of Cardiovascular Death, Myocardial Infarction (MI), Stroke, and All-Cause Mortality With Inhaled Anticholinergics

References

Global Initiative for Chronic Obstructive Lung Disease.  Global strategy for the diagnosis, management and prevention of COPD. http://www.goldcopd.org. Accessed August 5, 2008
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study.  Lancet. 1997;349(9064):1498-1504
PubMed   |  Link to Article
Boehringer Ingelheim.  Annual report 2007. http://www.boehringer-ingelheim.com/corporate/download/ar/AR2007.pdf. Accessed August 5, 2008
Anthonisen NR, Connett JE, Enright PL, Manfreda J.Lung Health Study Research Group.  Hospitalizations and mortality in the Lung Health Study.  Am J Respir Crit Care Med. 2002;166(3):333-339
PubMed   |  Link to Article
Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety.  Chest. 2006;130(6):1695-1703
PubMed   |  Link to Article
US Food and Drug Administration.  Early communication about an ongoing safety review of tiotropium (marketed as Spiriva Handihaler). http://www.fda.gov/cder/drug/early_comm/tiotropium.htm. Accessed August 5, 2008
Boehringer Ingelheim International.  Trial results. http://trials.boehringer-ingelheim.com/com/Home/TrialResults/index.jsp. Accessibility verified August 20, 2008
Barr RG, Bourbeau J, Camargo CA, Ram FSF. Tiotropium for stable chronic obstructive pulmonary disease.  Cochrane Database Syst Rev. 2005;(2):CD002876
PubMed
Barr RG, Bourbeau J, Camargo CA, Ram FSF. Tiotropium for stable chronic obstructive pulmonary disease: a meta-analysis.  Thorax. 2006;61(10):854-862
PubMed   |  Link to Article
Wilt TJ, Niewoehner D, MacDonald R, Kane RL. Management of stable chronic obstructive pulmonary disease: a systematic review for a clinical practice guideline.  Ann Intern Med. 2007;147(9):639-653
PubMed   |  Link to Article
Rodrigo GJ, Nannini LJ. Tiotropium for the treatment of stable chronic obstructive pulmonary disease: a systematic review with meta-analysis.  Pulm Pharmacol Ther. 2007;20(5):495-502
PubMed   |  Link to Article
Salpeter SR, Buckley NS, Salpeter EE. Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD.  J Gen Intern Med. 2006;21(10):1011-1019
PubMed   |  Link to Article
Loke YK, Price D, Herxheimer A.Cochrane Adverse Effects Subgroup. Including adverse effects. In: Cochrane Handbook for Systematic Reviews of Interventions. Chichester, England: John Wiley & Sons; 2006: Appendix 6b
Antithrombotic Trialists' Collaboration.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.  BMJ. 2002;324(7329):71-86
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Rosenberg MS. The file-drawer problem revisited: a general weighted method for calculating fail-safe numbers in meta-analysis.  Evolution. 2005;59(2):464-468
PubMed
Dr Chris Cates' EBM Web site. http://www.nntonline.net. Accessed August 5, 2008
McQuay HJ, Moore RA. Using numerical results from systematic reviews in clinical practice.  Ann Intern Med. 1997;126(9):712-720
PubMed   |  Link to Article
Casaburi R, Mahler DA, Jones PW,  et al.  A long-term evaluation of once daily-inhaled tiotropium in chronic obstructive pulmonary disease.  Eur Respir J. 2002;19(2):217-224
PubMed   |  Link to Article
Wedzicha JA, Calverley PMA, Seemungal TA,  et al.  The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.  Am J Respir Crit Care Med. 2008;177(1):19-26
PubMed   |  Link to Article
Powrie DJ, Wilkinson TMA, Donaldson GC,  et al.  Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.  Eur Respir J. 2007;30(3):472-478
PubMed   |  Link to Article
Chan CK, Maltais F, Sigouin C, Haddon JM, Ford GT.SAFE Study Group.  A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease.  Can Respir J. 2007;14(8):465-472
PubMed
Casaburi R, Briggs DD Jr, Donohue JF, Serby CW, Menjoge SS, Witek TJ Jr.US Tiotropium Study Group.  The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial.  Chest. 2000;118(5):1294-1302
PubMed   |  Link to Article
Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD [published correction appears in Thorax. 2005;60(2):105].  Thorax. 2003;58(5):399-404
PubMed   |  Link to Article
Donohue JF, van Noord JA, Bateman ED,  et al.  A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.  Chest. 2002;122(1):47-55
PubMed   |  Link to Article
Covelli H, Bhattacharya S, Cassino C, Conoscenti C, Kesten S. Absence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary disease.  Pharmacotherapy. 2005;25(12):1708-1718
PubMed   |  Link to Article
Niewoehner DE, Rice K, Cote C,  et al.  Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.  Ann Intern Med. 2005;143(5):317-326
PubMed   |  Link to Article
Bateman ED, van Dyk M, Sagriotis A. Comparable spirometric efficacy of tiotropium compared with salmeterol plus fluticasone in patients with COPD: a pilot study.  Pulm Pharmacol Ther. 2008;21(1):20-25
PubMed   |  Link to Article
Moita J, Bárbara C, Cardoso J,  et al.  Tiotropium improves FEV1 in patients with COPD irrespective of smoking status [published ahead of print May 18, 2007].  Pulm Pharmacol Ther. 2008;21(1):146-151
PubMed   |  Link to Article
Voshaar T, Lapidus R, Maleki-Yazdi R,  et al.  A randomized study of tiotropium respimat® soft MistTM inhaler vs. ipratropium pMDI in COPD.  Respir Med. 2008;102(1):32-41
PubMed   |  Link to Article
Combivent Inhalation Aerosol Study Group.  In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial.  Chest. 1994;105(5):1411-1419
PubMed   |  Link to Article
GlaxoSmithKline.  Clinical trial register for a multicenter, randomized, double-blind, double-dummy, parallel group, 8-week comparison of salmeterol xinafoate versus ipratropium bromide versus salmeterol xinafoate plus ipratropium bromide versus placebo in subjects with chronic obstructive pulmonary disease. http://ctr.gsk.co.uk/Summary/salmeterol/IV_SMS40315.pdf. Accessed August 5, 2008
GlaxoSmithKline.  Clinical trial register for a multicenter, randomized, double-blind, double-dummy, parallel-group, 8-week comparison of salmeterol xinafoate versus ipratropium bromide versus salmeterol xinafoate plus ipratropium bromide versus placebo in subjects with chronic obstructive pulmonary disease. http://ctr.gsk.co.uk/Summary/salmeterol/IV_SMS40314.pdf. Accessed August 5, 2008
Mahler DA, Donohue JF, Barbee RA,  et al.  Efficacy of salmeterol xinafoate in the treatment of COPD.  Chest. 1999;115(4):957-965
PubMed   |  Link to Article
Curkendall SM, DeLuise C, Jones JK,  et al.  Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan, Canada, cardiovascular disease in COPD patients.  Ann Epidemiol. 2006;16(1):63-70
PubMed   |  Link to Article
Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis.  Chest. 2004;125(6):2309-2321
PubMed   |  Link to Article
Macie C, Wooldrage K, Manfreda J, Anthonisen N. Cardiovascular morbidity and the use of inhaled bronchodilators.  Int J Chron Obstruct Pulmon Dis. 2008;3(1):163-169
PubMed
Lee TA.US Department of Veterans Affairs.  Outcomes associated with salmeterol use in obstructive lung disease (September 2007). http://www.hsrd.research.va.gov/research/abstracts.cfm?Project_ID=2141694968&UnderReview=no. Accessed August 5, 2008
Jara M, Lanes SF, Wentworth C III, May C, Kesten S. Comparative safety of long-acting inhaled bronchodilators: a cohort study using the UK THIN primary care database.  Drug Saf. 2007;30(12):1151-1160
PubMed   |  Link to Article
de Luise C, Lanes SF, Jacobsen J, Pedersen L, Sørensen HT. Cardiovascular and respiratory hospitalizations and mortality among users of tiotropium in Denmark.  Eur J Epidemiol. 2007;22(4):267-272
PubMed   |  Link to Article
Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? the potential role of systemic inflammation in chronic obstructive pulmonary disease.  Circulation. 2003;107(11):1514-1519
PubMed   |  Link to Article
Boekholdt SM, Peters RJ, Hack CE,  et al.  IL-8 plasma concentrations and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study.  Arterioscler Thromb Vasc Biol. 2004;24(8):1503-1508
PubMed   |  Link to Article
Ebi-Kryston KL. Respiratory symptoms and pulmonary function as predictors of 10-year mortality from respiratory disease, cardiovascular disease, and all causes in the Whitehall Study.  J Clin Epidemiol. 1988;41(3):251-260
PubMed   |  Link to Article
Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease.  J Am Coll Cardiol. 2006;47(12):2554-2560
PubMed   |  Link to Article
Decramer M, Celli B, Tashkin DP,  et al.  Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: the UPLIFT trial.  COPD. 2004;1(2):303-312
PubMed   |  Link to Article
Calverley PMA, Anderson JA, Celli B,  et al.  Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.  N Engl J Med. 2007;356(8):775-789
PubMed   |  Link to Article
Sidney S, Sorel M, Quesenberry CP Jr,  et al.  COPD and incident cardiovascular disease hospitalizations and mortality: Kaiser Permanente medical care program.  Chest. 2005;128(4):2068-2075
PubMed   |  Link to Article
Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD.  Chest. 2005;128(4):2640-2646
PubMed   |  Link to Article
Mannino DM. Epidemiology and global impact of chronic obstructive pulmonary disease.  Semin Respir Crit Care Med. 2005;26(2):204-210
PubMed   |  Link to Article
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