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Cardiovascular Events Associated With Ipratropium Bromide in COPD

Chest - Volume 137, Issue 1 (January 2010) - Copyright © 2010 The American College of Chest Physicians
DOI: 10.1378/chest.08-2367

Original Research
COPD
Cardiovascular Events Associated With Ipratropium Bromide in COPD

Sarika S. Ogale, PhD 1

Todd A. Lee, PharmD, PhD *
David H. Au, MD, MS
Denise M. Boudreau, PhD
Sean D. Sullivan, PhD

From the Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy (Drs Ogale, Boudreau, and Sullivan), University of Washington,
Seattle, WA; Center for Management of Complex Chronic Care (Dr Lee), Hines VA Hospital, Hines, IL; Center for Pharmacoeconomic Research and
Department of Pharmacy Practice (Dr Lee), University of Illinois at Chicago, Chicago, IL; Health Services Research and Development, VA Puget Sound Health
Care System and Department of Medicine (Dr Au), University of Washington, Seattle, WA; and The Center for Health Studies (Dr Boudreau), Group Health
Cooperative, Seattle, WA

* Correspondence to: Todd A. Lee, PharmD, PhD, Hines VA Hospital,

5000 S. 5 th Ave (151-H), Hines, IL 60141
1 Dr Ogale is currently at Genentech Pharmaceuticals, San Francisco, CA.

E-mail address: todd.lee@va.gov

Manuscript received October 1, 2008 , accepted February 12, 2009

Funding/Support: This research was funded by the US Department of Veterans Affairs Health Services Research and Development (IIR 03-
307).Reproduction of this article is prohibited without written permission from the American College of Chest Physicians
(www.chestjournal.org/site/misc/reprints.xhtml ).

PII S0012-3692(10)60009-8

Background
Studies have suggested an increased risk of cardiovascular morbidity and mortality associated with the use of
ipratropium bromide. We sought to examine the association between ipratropium bromide use and the risk of
cardiovascular events (CVEs).

Methods
We performed a cohort study of 82,717 US veterans with a new diagnosis of COPD between 1999 and 2002.
Subjects were followed until they had their first hospitalization for a CVE (acute coronary syndrome, heart failure, or
cardiac dysrhythmia), they died, or the end of the study period (September 30, 2004). Cumulative anticholinergic
exposure was calculated as the number of 30-day equivalents (ipratropium bromide) within the past year. We used
Cox regression models with time-dependent covariates to estimate the risk of CVE associated with anticholinergic
exposure and to adjust for potential confounders, including markers of COPD severity and cardiovascular risk.

Results

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We identified 6,234 CVEs (44% heart failure, 28% acute coronary syndrome, 28% dysrhythmia). Compared with
subjects not exposed to anticholinergics within the past year, any exposure to anticholinergics within the past 6
months was associated with an increased risk of CVE (hazard ratio [95% CI] for≤four and>four 30-day equivalents:
1.40 [1.30–1.51] and 1.23 [1.13–1.36], respectively). Among subjects who received anticholinergics more than 6
months prior, there did not appear to be elevated risk of a CVE.

Conclusions
We found an increased risk of CVEs associated with the use of ipratropium bromide within the past 6 months. These
findings are consistent with previous concerns raised about the cardiovascular safety of ipratropium bromide.

Abbreviations
CVD

cardiovascular disease

CVE

cardiovascular event

HR

hazard ratio

ICD-9-CM

International Statistical Classification of Diseases, ninth revision, Clinical Modification

ICS

inhaled corticosteroid

LABA

long-acting β 2 -agonists

LHS

Lung Health Study

RR

relative risk

SABA

short-acting β 2 -agonist

UPLIFT

Understanding Potential Long-term Impacts on Function with Tiotropium

VA

Veterans Affairs

Inhaled anticholinergic agents, such as ipratropium bromide and tiotropium bromide, have been shown to improve

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symptoms, reduce exacerbations, and improve quality of life in patients with COPD. [1] , [2] Because ipratropium
bromide is poorly absorbed from the gastrointestinal tract and lungs, systemic adverse effects such as tachycardia are
considered unlikely. [1] However, a link between anticholinergics and an increased risk of mortality, especially from
cardiovascular disease (CVD), has been reported. [3] , [4] , [5] , [6] , [7] Three studies highlighted potential
concerns between anticholinergics and cardiovascular safety in patients with COPD. Singh and colleagues [7] found in
their metaanalysis an increased risk for myocardial infarctions (relative risk [RR] 1.53, 95% CI, 1.05–2.23) and
cardiovascular death (RR 1.80, 1.17–2.77) in patients randomized to inhaled anticholinergics. Similarly, two
observational studies found increased risk between anticholinergic use and cardiovascular events (CVEs) [6] and
cardiovascular-related mortality. [5] In contrast, the recent Understanding Potential Long-term Impacts on Function
with Tiotropium (UPLIFT) study did not find an increase in cardiovascular adverse events in those randomized to
tiotropium. [2]

In the recent study, which focused on overall and cause-specific mortality, ipratropium bromide was associated with
increased risk of all-cause mortality (odds ratio 1.11, 1.08–1.15) and cardiovascular-related mortality (odds ratio 1.34,
1.22–1.47). [5] Some concerns regarding the accuracy of cause-specific mortality measurement may exist; therefore,
we felt it was important to examine the association between ipratropium bromide use and nonfatal cardiovascular end
points to more fully understand the potential risks associated with the medication. We performed a cohort study to
expand on our previous work and to examine the association between inhaled anticholinergic medications and CVEs
in patients with COPD. We also investigated the effect of inhaled corticosteroids (ICSs) and preexisting CVD on the
association of anticholinergics with CVEs.

Materials and Methods

We used national Veteran's Health Administration health-care databases for this analysis, including inpatient and
outpatient data, pharmacy data, and vital status information. The cohort in this analysis consisted of a subset of the
overall cohort we used to examine all-cause mortality. [5] This research was approved by the Hines VA Hospital and
University of Washington institutional review boards.

Cohort Identification
The cohort consisted of newly diagnosed patients with COPD who had at least one inpatient primary diagnosis or two
outpatient primary or secondary diagnoses of COPD (International Classification of Disease, ninth edition, Clinical
Modification [ICD-9-CM] 490–492.8, 496) within a 12-month period between October 1, 1998, and September 30,
2002. Cohort entry was marked by the date of the second outpatient encounter or the date of discharge for the first
hospitalization. Patients had to be between 40 and 100 years of age at cohort entry.

To identify the incident patients with COPD and not just patients new to the Veterans Affairs (VA) system, only
patients with at least one medical encounter but no COPD or asthma diagnosis (ICD-9-CM 490–493.9, 496) or drugs
(β2 -agonists, anticholinergics, methylxanthines, ICSs, cromones, or leukotriene modifiers) during the year prior to
cohort entry were included. We excluded patients who had a diagnosis of asthma (ICD-9-CM 493–493.9) or had been
dispensed an asthma drug not approved for COPD (cromones or leukotriene modifiers) at any time after cohort entry.
Subjects were followed until their first hospitalization for a CVE, death, or the end of the study period (September 30,
2004).

End Point Ascertainment

The primary end point of a CVE was defined as the first hospitalization after cohort entry with a primary diagnosis of
acute coronary syndrome (ICD-9-CM 410–411.89), heart failure (ICD-9-CM 425–425.4, 425.7–425.9, 402.01, 402.11,
402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.9), or cardiac dysrhythmia (ICD-9-CM 427–428.93, 785.0).

Characterization of Exposure
Time-dependent exposure to inhaled ipratropium bromide was characterized as exposed vs unexposed within the past
year, and recency of exposure and cumulative exposure within the past year. At each event occurrence, exposure
within the past year was recalculated for the subject experiencing the CVE as well as subjects who had been in the
cohort for the same amount of time as the failure, but had not experienced a CVE at that point (ie, those at risk).

Patients were classified as exposed if they had exposure to anticholinergics within the past year. Recency of exposure
was calculated as the number of months since the last exposure to anticholinergics. Cumulative exposure was

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calculated as the number of standard 30-day equivalents of inhaled anticholinergics potentially used within the past
year. A standard 30-day equivalent of inhaled anticholinergics was considered to be 36 µg of ipratropium bromide by
metered-dose inhaler or 0.5 mg by nebulizer four times daily, or 18 µg of tiotropium daily for 30 days.

Covariates
Non-time-dependent covariates defined at cohort entry included age (years), sex, race (black, white, other, or
missing), year of cohort entry (1999–2003), distance to nearest VA hospital, and cardiovascular risk factors such as
prior CVD, hypertension, hyperlipidemia, and diabetes during the year prior to cohort entry. The presence of these
risk factors was determined based on diagnoses and medications dispensed during the year prior to cohort entry.

We recorded the site of the initial diagnosis of COPD (inpatient or outpatient) as an indicator of COPD severity at
diagnosis. Time-dependent covariates used as markers of disease severity included the number of inpatient and
outpatient COPD exacerbations, and the standardized number of canisters of short-acting β 2 -agonists (SABAs) within
the past year. Indicator variables were created for the use of other respiratory drugs such as long-acting β 2 -agonists
(LABAs), ICSs, theophylline, supplemental oxygen, oral or nebulized β 2 -agonists, and nebulized anticholinergics
within the past year. We also created an indicator variable for the use of other anticholinergic agents in the past year.

An inpatient exacerbation was defined as hospitalization with a primary diagnosis code of COPD. An outpatient
exacerbation was defined as an outpatient visit with a primary diagnosis code of COPD followed by a prescription for
a ≤14-day course of either oral steroid or antibiotic that was filled within 48 h of the outpatient visit. [8] , [9] Two
exacerbations had to be separated by at least 30 days for both to be counted. [10]

Statistical Analysis
Multivariate Cox proportional hazards regression models were used to determine the association between exposure to
anticholinergics and the risk of CVEs, after adjusting for all non-time-dependent and time-dependent covariates. [11]
All three exposure characteristics were included in the same model. Adjusted hazard ratios (HRs) and 95% CIs
comparing different combinations of recency of exposure and cumulative exposure, against the never-exposed group
were calculated. We used likelihood ratio tests to examine effect-modification of the relationship between
anticholinergics and study end points by use of ICS within the past year and prior CVD. All statistical tests were two-
tailed and performed at an a priori ɑ-level of 0.05. Statistical analyses were conducted using STATA version 8
(STATA Corp; College Station, TX).

Results
Our cohort consisted of 82,717 patients newly diagnosed with COPD. During a total follow-up of 274,025 patient-
years, there were 6,234 CVEs, for a rate of 2.2 CVEs per 100 patient-years. A plurality of the CVE hospitalizations
were for heart failure (44%), while the remaining hospitalizations were split equally between acute coronary syndrome
and cardiac dysrhythmia. The cohort was predominantly male and white, with a mean age of 66.7 years (Table 1).
More than 50% of the patients resided more than 25 miles from a VA hospital. Three-quarters had at least one
cardiovascular risk factor at cohort entry. Most patients received their initial diagnosis of COPD in the outpatient
setting.

Table 1 -- Baseline Characteristics of the Study Cohort Characteristics

Patients, No. (%) Patient-Years (%) CVEs, No. (%) Adjusted HR [a]
Entire cohort 82,717 (100) 274,025 (100) 6,234
Demographics
 Age at diagnosis, mean (SD), y 66.8 (11.2) 1.02 (1.01–1.03)
  ≤65 34,864 (42) 125,146 (46) 1,948 (31)
  >65 47,853 (58) 148,878 (54) 4,286 (69)
 Sex
  Male 80,418 (97) 265,775 (97) 6,149 (99) 1.70 (1.37–2.10)

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  Female 2,299 (3) 8,249 (3) 85 (1) Reference

 Race
  White 54,821 (66) 179,800 (66) 4,839 (78) Reference
  Black 8,578 (13) 27,815 (10) 851 (14) 1.03 (0.96–1.12)
  Other 454 (1) 1,557 (1) 39 (1) 0.95 (0.69–1.30)
  Missing 18,864 (23) 64,852 (24) 505 (8) 0.36 (0.33–0.40)
 Distance from the nearest VA hospital
  ≤5 miles 13,751 (17) 44,816 (16) 1,432 (23) Reference
  5 to<10 miles 10,898 (13) 35,146 (13) 1,094 (18) 0.98 (0.91–1.06)
  10 to<25 miles 15,778 (19) 52,091 (19) 1,319 (21) 0.82 (0.76–0.88)
  25 to<100 miles 36,774 (44) 123,077 (45) 2,192 (35) 0.59 (0.55–0.64)
  ≥100 miles 5,516 (7) 18,894 (7) 197 (3) 0.38 (0.32–0.44)
Cardiovascular risk factors within the year prior to cohort entry
 CVD [b]
  Yes 41,859 (51) 129,800 (47) 4,833 (78) 2.50 (2.31–2.69)
  No 40,858 (49) 144,225 (53) 1,401 (22) Reference
 Hypertension [c]
  Yes 54,508 (66) 173,365 (63) 5,285 (85) 1.66 (1.53–1.79)
  No 28,209 (34) 100,660 (37) 949 (15) Reference
 Hyperlipidemia [d]
  Yes 26,883 (32) 85,697 (31) 2,550 (41) 0.95 (0.90–1.00)
  No 55,834 (68) 188,328 (69) 3,684 (59) Reference
 Diabetes [e]
  Yes 52,439 (63) 162,463 (59) 3,444 (55) 1.12 (1.05–1.19)
  No 30,278 (37) 104,058 (38) 2,790 (45) Reference
Marker of COPD severity at diagnosis
 Site of new COPD diagnosis:
  Inpatient 3,050 (4) 8,381 (3) 498 (8) Reference
  Outpatient 79,667 (96) 265,644 (97) 5,736 (92) 0.51 (0.47–0.57)

CVD = cardiovascular disease; CVE = cardiovascular event; HR = hazard ratio; VA = Veterans Affairs.

a Adjusted HRs from the final model with all baseline and time-dependent variables including anticholinergic exposure.

b Patients had a CVD if they met at least one of the following criteria: one primary inpatient diagnosis, two outpatient diagnoses, one
cardiovascular procedure, or one prescription for a CVD drug.
c Patients had hypertension if they met at least one of the following criteria: two outpatient diagnoses, one outpatient diagnosis and one
prescription for an antihypertensive, or two prescriptions for antihypertensives.
d Patients had hyperlipidemia if they met at least one of the following criteria: two outpatient diagnoses, or one prescription for an
antihyperlipidemic drug.
e Patients had diabetes if they met at least one of the following criteria: one primary inpatient diagnosis, two outpatient diagnoses, or one
prescription for an antidiabetic drug.

Forty percent of the cohort received no COPD medication during the study. More than 44% were exposed to
anticholinergics at some time during the study period. Of those exposed to anticholinergics, 36% also received ICS,

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18% LABAs, 6% theophylline, and 93% SABAs. A total of 329,255 prescriptions were dispensed for anticholinergic
agents. Only 78 were for tiotropium, while the remaining prescriptions were for ipratropium bromide alone by metered-
dose inhaler (55%) or nebulization (7%), or ipratropium bromide in a fixed-dose combination with albuterol (38%).

Overall, exposure to anticholinergics was associated with a 29% higher risk of CVEs relative to no exposure in the
past year. The crude and adjusted HRs comparing various combinations of recency of exposure and cumulative
exposure to anticholinergics are presented in Table 2. Adjusting for baseline (non-time-dependent) covariates slightly
reduced the HRs, which were further reduced after adjusting for all potential confounders, including time-dependent
covariates. For patients whose last anticholinergic exposure occurred within the past 6 months, a cumulative
exposure of≤four 30-day equivalents of anticholinergics was associated with a 40% increase in the risk of CVEs,
while>four 30-day equivalents were associated with a 23% increase in risk, relative to patients unexposed to
anticholinergics within the past year. There was no significant association between anticholinergic exposure and CVEs
if the exposure occurred more than 6 months prior.

Table 2 -- Crude and Adjusted HRs for CVE

Final Adjusted HR Model [b]
Characteristics Crude HR (95% Baseline Adjusted HR (95% HR (95% CI) P Value
CI) CI) [a]
Unexposed to anticholinergics 1.00 1.00 1.00 …
Exposed to anticholinergics 1.48 (1.40–1.56) 1.47 (1.39–1.55) 1.29 (1.21–1.38) <.01
Recency of exposure: past 6
mo
 Anticholinergic equivalents (≤4) 1.55 (1.44–1.66) 1.51 (1.41–1.62) 1.40 (1.30–1.51) <.01
 Anticholinergic equivalents (>4) 1.49 (1.39–1.60) 1.52 (1.42–1.63) 1.23 (1.12–1.35) <.01
Recency of exposure: > 6 mo
 Anticholinergic equivalents (≤4) 1.17 (1.02–1.35) 1.13 (0.98–1.29) 1.08 (0.94–1.24) .27
 Anticholinergic equivalents (>4) 1.13 (0.96–1.33) 1.14 (0.97–1.34) 0.95 (0.80–1.12) .57

See Table 1 for expansion of abbreviations.

a Adjusted for all baseline variables from Table 1 and fiscal year of cohort entry.
b Adjusted for all baseline variables from Table 1 , fiscal year of cohort entry, and all time-dependent variables from Figure 1 .

Effect modification by the presence of CVD at baseline (Table 3) was statistically significant (Likelihood Ratio test: P
value=0.01). In all categories of anticholinergic exposure, except patients who received ≤ four 30-day equivalents and
were last exposed within the past 6 months, the HRs for CVE were higher in patients without prior CVD. Even
though effect modification by ICS use within the past year was not statistically significant (likelihood ratio test: P
value=0.13), the HRs of CVE were consistently higher in patients who had received ICS in the past year, across all
anticholinergic exposure categories.

Table 3 -- Adjusted HRs for CVEs Stratified By Prior CVD and ICS Use
No Prior CVD Prior CVD
Adjusted HR (95% CI) P Value Adjusted HR (95% CI) P Value
Unexposed to anticholinergics 1.00 … 1.00 …
Recency of exposure: ≤6 mo
 Anticholinergic equivalents (≤4) 1.36 (1.16–1.59) <.01 1.41 (1.30–1.53) <.01
 Anticholinergic equivalents (>4) 1.46 (1.26–1.70) <.01 1.17 (1.06–1.29) <.01

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Recency of exposure: >6 mo

 Anticholinergic equivalents (≤4) 1.25 (0.95–1.63) .10 1.03 (0.87–1.21) .70
 Anticholinergic equivalents (>4) 1.34 (0.98–1.84) .06 0.85 (0.70–1.03) .10
ICS use No ICS use in past year ICS use in past year
Recency of exposure: ≤6 mo
 Anticholinergic equivalents (≤4) 1.35 (1.25–1.47) <.01 1.79 (1.43–2.23) <.01
 Anticholinergic equivalents (>4) 1.22 (1.10–1.35) <.01 1.42 (1.15–1.75) <.01
Recency of exposure: >6 mo
 Anticholinergic equivalents (≤4) 1.07 (0.92–1.24) .36 1.25 (0.88–1.79) .20
 Anticholinergic equivalents (>4) 0.96 (0.80–1.16) .73 0.99 (0.68–1.46) .99

ICS=inhaled corticosteroid. See Table 1 for expansion of other abbreviations.

Only 3.4% of the study cohort had at least one COPD exacerbation requiring hospitalization during the study, and
17% had an outpatient exacerbation. Figure 1 shows the HRs of CVE for the time-dependent covariates in our fully
adjusted Cox regression model. Each additional inpatient exacerbation doubled the risk of CVEs. A 28% increase in
the risk of CVEs was associated with each additional outpatient exacerbation, as well as with the use of oral or
nebulized β 2 -agonists within the past year.

Figure 1 Adjusted HR of CVE for time-dependent covariates. CVE=cardiovascular event; HR=hazard ratio;
ICS=inhaled corticosteroid; Inpat exacer=inpatient exacerbations; LABA=long-acting β 2 -agonist; Neb
antichol.=nebulized anticholinergics; Neb BA=nebulized β-agonists; Outpat exacer=outpatient exacerbations; Other
antichol=other anticholinergics; SABA=short-acting β 2 -agonist; SABA cans=SABA cannisters; Theo=Theophylline.

Discussion
We conducted a cohort study to examine the association between anticholinergic use and CVEs in a cohort with
newly diagnosed COPD. In our study, we found an increased risk of CVE associated with the use of ipratropium
bromide in patients with COPD. We found a significant effect of recency of exposure to ipratropium bromide on CVE
risk, where the increased risk was limited to patients exposed to anticholinergics within the past 6 months. These
results are consistent with our previous work that found an association between ipratropium bromide use and
cardiovascular-related mortality. These findings may help alleviate concerns about misclassification of cardiovascular-
related mortality as ipratropium bromide was associated with both an increased risk of events and cardiovascular-
related mortality. Thus, we showed that ipratropium bromide may be associated with a mechanism for cardiovascular-
related deaths.

These results are also consistent with results from other recent studies. A recent metaanalysis showed an increased

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risk for myocardial infarctions (RR 1.53, 95% CI, 1.05–2.23) and cardiovascular death (RR 1.80, 1.17–2.77) in
patients randomized to inhaled anticholinergics. [7] An observational study in Canada showed an increased risk of
cardiovascular hospitalizations associated with ipratropium bromide. [6] Each of these results support the findings of
the Lung Health Study (LHS), which reported a higher risk of CVD deaths and supraventricular tachycardia in patients
receiving ipratropium bromide. [3] The LHS also found a dose-effect relationship, with supraventricular tachycardia
occurring mostly in patients that were more adherent to their ipratropium bromide treatment, thus supporting the
possibility of a causal relationship. Also, Guite and colleagues [4] reported patients with prescriptions of ipratropium
bromide after discharge from an asthma-related hospitalization were associated with a 3.35-fold increase (95% CI,
1.05 to 11.94) in risk of death from CVD.

In contrast, Ringbaek and Viskum [12] found no increase in the risk of CVD-related deaths with the use of ipratropium
bromide in patients with COPD, even though there was a 1.6-fold (95% CI, 1.2 to 2.1) increased risk of all-cause
mortality in ipratropium bromide users, compared with nonusers. A pooled analysis of five clinical trials showed a 73%
reduction in the risk of respiratory-related deaths with the use of anticholinergic agents compared with placebo in
COPD. [13] Deaths related to CVD and all-cause mortality were not evaluated. The LHS was the only study in the
pooled analysis that identified respiratory deaths in ipratropium bromide users; the other four trials compared
tiotropium with placebo. The recently reported UPLIFT study did not show an increased risk of cardiac adverse
events when comparing tiotropium with placebo. Importantly, our current analysis focused on ipratropium bromide and
not tiotropium as only 78 prescriptions for tiotropium were dispensed to this cohort during the study period. Also, in
the UPLIFT study nearly 50% of those included in the study were using anticholinergics prior to enrollment in the
study, which may impact their susceptibility to adverse events associated with anticholinergics. In our study, we focus
on newly diagnosed patients in order to identify new exposure to respiratory medications when examining the
association with adverse events.

In most cases, risks for CVE in this analysis were higher in patients who had no CVD at baseline compared with
those who had CVD at baseline. This was an unanticipated finding as we expected patients with preexisting CVD to
be more vulnerable to the potential cardiac adverse effects of anticholinergics. On the other hand, it is possible that
because prior CVD is a major independent risk factor (RR 2.5, 95% CI, 2.31–2.69) for CVEs, the addition of
anticholinergics in these patients does not increase their risk of CVE further. Alternatively, the absence of an ICD-9-
CM code and prescription for CVD may be a result of undiagnosed or untreated CVD for some patients, putting them
at a higher risk of cardiovascular adverse effects of anticholinergic medications.

The strengths of our study include a large cohort with a potential follow-up of over 5 years for some patients,
comprehensive prescription-dispensing data for patients who fill their prescriptions within the VA system, time-
dependent exposure measurement to capture real-world prescription patterns, and multiple resource utilization
measures used as markers of COPD severity.

There were several limitations to our study. In this analysis, we did not include non-VA hospitalization data for
patients, nor did we have information on the cause of death for the entire cohort. Thus, if patients suffered sudden
cardiac death outside the hospital setting or if they were admitted to the nearest non-VA hospital for an emergency
CVE, their event would not be captured in our study. Some patients who had an event would be misclassified as not
having an event, leading to less than perfect sensitivity for the identification of CVEs. We do not believe that such
misclassification would be differential between exposure categories. We adjusted for the distance to the nearest VA
hospital from the patient's residence and found that increasing distance from a VA hospital was associated with a
decreasing risk of hospitalization for CVEs (see Table 1), confirming previous findings that patients living farther away
from a VA hospital would be more likely to seek care at a non-VA facility in a medical emergency. [14]
Misclassification of exposure is also possible. If pharmacy records show that a certain quantity of anticholinergics was
dispensed to the patient, we assume that the medication was consumed completely as dispensed. If patients used
only a portion or none of their dispensed medication, we would wrongly classify those patients into the exposed
category or into higher cumulative exposure categories. This would result in dilution of the true effect of exposure and
bias toward the null.

We did not have data on several risk factors, such as smoking status, laboratory measures for hypertension,
hyperlipidemia and diabetes, and BMI. There is the potential for channeling bias to exist for ipratropium bromide if
patients with risk factors for CVD are differentially prescribed ipratropium bromide in order to avoid β-agonists. This is
one of the reasons we conducted a stratified analysis by the presence of cardiovascular risk factors. If the findings
were solely a result of channeling bias, we would not have expected to see an increased risk associated with
ipratropium bromide in those without markers of CVD. Additionally, we controlled for SABA use in the analysis and

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found that only 18% of the patients in the cohort received LABAs during the study period. While these issues do not
completely alleviate concerns of channeling bias, because we are unable to measure all of the potentially important
risk factors (eg, weight, low-density lipoprotein, high-density lipoprotein), taken together they may minimize overall
concerns about differential prescribing and risk.

In most COPD guidelines, including those used in the VA healthcare system, ipratropium bromide is considered a
first-line medication for newly diagnosed patients with COPD. Other medications are added as the disease
progresses. Thus, we do not expect patients receiving ipratropium bromide to have more severe COPD than patients
receiving other drugs, and it is unlikely that the excess risk of CVE associated with anticholinergic exposure is solely
the result of confounding by severity. We observed a trend toward higher HRs associated with ipratropium bromide
use among patients who also received ICS. Because ICS use may be an indicator of higher disease severity,
confounding by severity could account for this finding. Even though we adjusted for disease severity using several
resource utilization measures, the possibility of residual confounding by disease severity cannot be completely ruled
out. We did not have information on pulmonary function and hence could not classify patients into disease severity
categories as per the Global Initiative for Chronic Obstructive Lung Disease guidelines.

In conclusion, our study found that filling a prescription for ipratropium bromide within the past 6 months was
associated with an elevated risk of CVE. This finding supports our previous work on the association between
ipratropium bromide and cardiovascular-related deaths as it links an increased risk of events with exposure to the
medication. Importantly, this study does not evaluate potential benefits associated with the use of ipratropium
bromide. It remains important for clinicians and patients to be aware of the potential benefits as well as the risks
when making medication decisions for the treatment of COPD.

Acknowledgments
Author contributions:Dr Ogale: had full access to all the data and takes responsibility for the integrity of the data
and the accuracy of the data analysis, contributed to the study concept and design, analyzed and interpreted the
data, drafted the manuscript, critically revised the manuscript for important intellectual content, and contributed to the
statistical analysis.

Dr Lee: had full access to all the data and takes responsibility for the integrity of the data and the accuracy of the
data analysis, contributed to the study concept and design, acquired the data, analyzed and interpreted the data,
critically revised the manuscript for important intellectual content, contributed to the statistical analysis, obtained
funding, provided administrative, technical, or material support, and supervised the study.

Dr Au: analyzed and interpreted the data, and critically revised the manuscript for important intellectual content.

Dr Boudreau: analyzed and interpreted the data, and critically revised the manuscript for important intellectual content.

Dr Sullivan: had full access to all the data and takes responsibility for the integrity of the data and the accuracy of the
data analysis, contributed to the study concept and design, analyzed and interpreted the data, critically revised the
manuscript for important intellectual content, provided administrative, technical, or material support, and supervised
the study.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Drs Lee
and Sullivan have received funding for their contribution to the Burden of Obstructive Lung Disease (BOLD) Initiative,
which has been funded in part by unrestricted educational grants to the Operations Center (www.boldcopd.org )
from ALTANA, Aventis, AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Merck, Novartis, Pfizer,
Schering-Plough, Sepracor, and the University of Kentucky. Drs Lee and Sullivan have received past research grants
from AstraZeneca, Boehringer-Ingelheim, Pfizer, Novartis, and GlaxoSmithKline. Dr Lee has participated in past
advisory boards for AstraZeneca and Novartis. Drs Ogale, Au, and Boudreau have reported no potential conflicts of
interest with any companies/organizations whose products or sevices may be discussed in this article.

Role of sponsors: The US Department of Veterans Affairs had no role in the design, analysis, interpretation, or
reporting of results. The views expressed in this article are those of the authors and do not necessarily reflect the
position or policy of the US Department of Veterans Affairs.

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