Cardiovascular Events Associated With Ipratropium Bromide in COPD Sarika S. Ogale, Todd A. Lee, David H. Au, Denise M. Boudreau and Sean D. Sullivan Chest 2010;137;13-19; Prepublished online April 10, 2009; DOI 10.1378/chest.08-2367
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CHEST
Original Research COPD
Cardiovascular Events Associated With Ipratropium Bromide in COPD Sarika S. Ogale, PhD; Todd A. Lee, PharmD, PhD; David H. Au, MD, MS; Denise M. Boudreau, PhD; and Sean D. Sullivan, PhD
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: 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 ⱕ 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. CHEST 2010; 137(1):13–19 Abbreviations: CVD 5 cardiovascular disease; CVE 5 cardiovascular event; HR 5 hazard ratio; ICD-9-CM 5 International Statistical Classification of Diseases, ninth revision, Clinical Modification; ICS 5 inhaled corticosteroid; LABA 5 long-acting b2-agonists; LHS 5 Lung Health Study; RR 5 relative risk; SABA 5 short-acting b2-agonist; UPLIFT 5 Understanding Potential Long-term Impacts on Function with Tiotropium; VA 5 Veterans Affairs
anticholinergic agents, such as ipratropium Inhaled bromide and tiotropium bromide, have been shown
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
Manuscript received October 1, 2008; revision accepted February 12, 2009. Affiliations: 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. Dr Ogale is currently at Genentech Pharmaceuticals, San Francisco, CA. Funding/Support: This research was funded by the US Department of Veterans Affairs Health Services Research and Development (IIR 03-307).
For editorial comment see page 1
to improve symptoms, reduce exacerbations, and improve quality of life in patients with COPD.1,2
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increased risk of mortality, especially from cardiovascular disease (CVD), has been reported.3-7 Three studies highlighted potential concerns between anticholinergics and cardiovascular safety in patients with Correspondence to: Todd A. Lee, PharmD, PhD, Hines VA Hospital, 5000 S. 5th Ave (151-H), Hines, IL 60141; e-mail: todd.lee@ va.gov © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.08-2367 CHEST / 137 / 1 / JANUARY, 2010
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COPD. Singh and colleagues7 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 (b2-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 493493.9) 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 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 mg of ipratropium bromide by metered-dose inhaler or 0.5 mg by nebulizer four times daily, or 18 mg 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 b2-agonists (SABAs) within the past year. Indicator variables were created for the use of other respiratory drugs such as long-acting b2-agonists (LABAs), ICSs, theophylline, supplemental oxygen, oral or nebulized b2-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 âą• 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-timedependent 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
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recency of exposure and cumulative exposure, against the neverexposed 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 a-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. (%) Entire cohort Demographics Age at diagnosis, mean (SD), y ⱕ 65 . 65 Sex Male Female Race White Black Other Missing Distance from the nearest VA hospital ⱕ 5 miles 5 to , 10 miles 10 to , 25 miles 25 to , 100 miles ⱖ100 miles Cardiovascular risk factors within the year prior to cohort entry CVDb Yes No Hypertensionc Yes No Hyperlipidemiad Yes No Diabetese Yes No Marker of COPD severity at diagnosis Site of new COPD diagnosis: Inpatient Outpatient
Patient-Years (%)
CVEs, No. (%)
Adjusted HRa
82,717 (100)
274,025 (100)
6,234
66.8 (11.2) 34,864 (42) 47,853 (58)
125,146 (46) 148,878 (54)
1,948 (31) 4,286 (69)
80,418 (97) 2,299 (3)
265,775 (97) 8,249 (3)
6,149 (99) 85 (1)
1.70 (1.37-2.10) Reference
54,821 (66) 8,578 (13) 454 (1) 18,864 (23)
179,800 (66) 27,815 (10) 1,557 (1) 64,852 (24)
4,839 (78) 851 (14) 39 (1) 505 (8)
Reference 1.03 (0.96-1.12) 0.95 (0.69-1.30) 0.36 (0.33-0.40)
13,751 (17) 10,898 (13) 15,778 (19) 36,774 (44) 5,516 (7)
44,816 (16) 35,146 (13) 52,091 (19) 123,077 (45) 18,894 (7)
1,432 (23) 1,094 (18) 1,319 (21) 2,192 (35) 197 (3)
Reference 0.98 (0.91-1.06) 0.82 (0.76-0.88) 0.59 (0.55-0.64) 0.38 (0.32-0.44)
41,859 (51) 40,858 (49)
129,800 (47) 144,225 (53)
4,833 (78) 1,401 (22)
2.50 (2.31-2.69) Reference
54,508 (66) 28,209 (34)
173,365 (63) 100,660 (37)
5,285 (85) 949 (15)
1.66 (1.53-1.79) Reference
26,883 (32) 55,834 (68)
85,697 (31) 188,328 (69)
2,550 (41) 3,684 (59)
0.95 (0.90-1.00) Reference
52,439 (63) 30,278 (37)
162,463 (59) 104,058 (38)
3,444 (55) 2,790 (45)
1.12 (1.05-1.19) Reference
3,050 (4) 79,667 (96)
8,381 (3) 265,644 (97)
498 (8) 5,736 (92)
Reference 0.51 (0.47-0.57)
1.02 (1.01-1.03)
CVD 5 cardiovascular disease; CVE 5 cardiovascular event; HR 5 hazard ratio; VA 5 Veterans Affairs. aAdjusted HRs from the final model with all baseline and time-dependent variables including anticholinergic exposure. bPatients 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. cPatients 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. dPatients had hyperlipidemia if they met at least one of the following criteria: two outpatient diagnoses, or one prescription for an antihyperlipidemic drug. ePatients 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. www.chestjournal.org
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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, 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 ⱕ 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. Effect modification by the presence of CVD at baseline (Table 3) was statistically significant (Likelihood Ratio test: P value 5 0.01). In all categories of anticholinergic exposure, except patients who received ⱕ 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 5 0.13), the HRs of CVE were con-
sistently higher in patients who had received ICS in the past year, across all anticholinergic exposure categories. 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 b2-agonists within the past year.
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 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
Table 2—Crude and Adjusted HRs for CVE Final Adjusted HR Modelb Characteristics Unexposed to anticholinergics Exposed to anticholinergics Recency of exposure: past 6 mo Anticholinergic equivalents (ⱕ 4) Anticholinergic equivalents (. 4) Recency of exposure: . 6 mo Anticholinergic equivalents (ⱕ 4) Anticholinergic equivalents (. 4)
Crude HR (95% CI)
Baseline Adjusted HR (95% CI)a
HR (95% CI)
P Value
1.00 1.48 (1.40-1.56)
1.00 1.47 (1.39-1.55)
1.00 1.29 (1.21-1.38)
… , .01
1.55 (1.44-1.66) 1.49 (1.39-1.60)
1.51 (1.41-1.62) 1.52 (1.42-1.63)
1.40 (1.30-1.51) 1.23 (1.12-1.35)
, .01 , .01
1.17 (1.02-1.35) 1.13 (0.96-1.33)
1.13 (0.98-1.29) 1.14 (0.97-1.34)
1.08 (0.94-1.24) 0.95 (0.80-1.12)
.27 .57
See Table 1 for expansion of abbreviations. Adjusted for all baseline variables from Table 1 and fiscal year of cohort entry. bAdjusted for all baseline variables from Table 1, fiscal year of cohort entry, and all time-dependent variables from Figure 1. a
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Table 3—Adjusted HRs for CVEs Stratified By Prior CVD and ICS Use No Prior CVD Adjusted HR (95% CI) Unexposed to anticholinergics Recency of exposure: ⱕ 6 mo Anticholinergic equivalents (ⱕ 4) Anticholinergic equivalents (. 4) Recency of exposure: . 6 mo Anticholinergic equivalents (ⱕ 4) Anticholinergic equivalents (. 4) ICS use Recency of exposure: ⱕ 6 mo Anticholinergic equivalents (ⱕ 4) Anticholinergic equivalents (. 4) Recency of exposure: . 6 mo Anticholinergic equivalents (ⱕ 4) Anticholinergic equivalents (. 4)
Prior CVD P Value
Adjusted HR (95% CI)
P Value
1.00
…
1.00
…
1.36 (1.16-1.59) 1.46 (1.26-1.70)
, .01 , .01
1.41 (1.30-1.53) 1.17 (1.06-1.29)
, .01 , .01
1.25 (0.95-1.63) 1.34 (0.98-1.84) No ICS use in past year
.10 .06
1.03 (0.87-1.21) 0.85 (0.70-1.03) ICS use in past year
.70 .10
1.35 (1.25-1.47) 1.22 (1.10-1.35)
, .01 , .01
1.79 (1.43-2.23) 1.42 (1.15-1.75)
, .01 , .01
1.07 (0.92-1.24) 0.96 (0.80-1.16)
.36 .73
1.25 (0.88-1.79) 0.99 (0.68-1.46)
.20 .99
ICS 5 inhaled corticosteroid. See Table 1 for expansion of other abbreviations.
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 colleagues4 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 Viskum12 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.
Figure 1. Adjusted HR of CVE for time-dependent covariates. CVE 5 cardiovascular event; HR 5 hazard ratio; ICS 5 inhaled corticosteroid; Inpat exacer 5 inpatient exacerbations; LABA 5 long-acting b2-agonist; Neb antichol. 5 nebulized anticholinergics; Neb BA 5 nebulized b-agonists; Outpat exacer 5 outpatient exacerbations; Other antichol 5 other anticholinergics; SABA 5 short-acting b2-agonist; SABA cans 5 SABA cannisters; Theo 5 Theophylline. www.chestjournal.org
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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 realworld 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 b-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 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 cardiovascularrelated 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.
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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, BoehringerIngelheim, 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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CHEST / 137 / 1 / JANUARY, 2010
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Cardiovascular Events Associated With Ipratropium Bromide in COPD Sarika S. Ogale, Todd A. Lee, David H. Au, Denise M. Boudreau and Sean D. Sullivan Chest 2010;137; 13-19; Prepublished online April 10, 2009; DOI 10.1378/chest.08-2367 This information is current as of February 2, 2010 Updated Information & Services
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