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Atrovent (ipratropium) another killer

Drug News--disappointing

Ipratropium bromide used to tread COPD (cardio-pulmonary disease) increases mortality by cardiovascular death by 34%,   Corticosteriod reduce both cardiovascular and all causes of mortality by 20%

Annals of Internal Medicine tip sheet for Sept. 16, 2008, issue

September 17, 2008.  http://www.annals.org/cgi/content/full/149/6/380


The drug ipratropium bromide (Atrovent, Combivent) significantly raised the risk of mortality by cardiovascular death in patients undergoing COPD treatment, according to researchers. In addition, exposure to the medication theophylline was associated with an increased risk of respiratory death, but not cardiovascular death.

The Annals of Internal Medicine published the study findings in the September 16, 2008 issue. The findings are the result of a large-scale study of U.S. Veterans Health Administration health care system patient data.

Researchers followed a cohort of patients enrolled in the U.S. Veterans Health Administration health care system to assess mortality rates at one year.

Inhaled corticosteroids were associated with decreased risk for death, while theophyline and ipratropium were associated with increased risk for respiratory and cardiovascular death, respectively.  Ipratropium was associated with an 11 percent increase in the risk for death, raising researchers' concerns about the potential harm associated with the drug rather than simply a lack of effectiveness.

It remains unclear if the elevated risk applies to women or patients with longstanding or severe COPD. The researchers found a 34 percent increased risk of cardiovascular death and all-cause mortality in patients using the medication to relieve the symptoms of COPD.

On the other hand, inhaled corticosteroids, the researchers found, were associated with a 20 percent decrease in cardiovascular and all cause mortality.

Risk for Death Associated with Medications for Recently Diagnosed Chronic Obstructive Pulmonary Disease


Todd A. Lee, PharmD, PhD; A. Simon Pickard, PhD; David H. Au, MD, MS; Brian Bartle, MPH; and Kevin B. Weiss, MD, MPH, MS
16 September 2008 | Volume 149 Issue 6 | Pages 380-390

Background: Concerns exist regarding increased risk for mortality associated with some chronic obstructive pulmonary disease (COPD) medications.

Objective: To examine the association between various respiratory medications and risk for death in veterans with newly diagnosed COPD.

Design: Nested case–control study in a cohort identified between 1 October 1999 and 30 September 2003 and followed through 30 September 2004 by using National Veterans Affairs inpatient, outpatient, pharmacy, and mortality databases; Centers for Medicare & Medicaid Services databases; and National Death Index Plus data. Cause of death was ascertained for a random sample of 40% of those who died during follow-up. Case patients were categorized on the basis of all-cause, respiratory, or cardiovascular death. Mortality risk associated with medications was assessed by using conditional logistic regression adjusted for comorbid conditions, health care use, and markers of COPD severity.

Setting: U.S. Veterans Health Administration health care system.

Participants: 32 130 case patients and 320 501 control participants in the all-cause mortality analysis. Of 11 897 patients with cause-of-death data, 2405 case patients had respiratory deaths and 3159 case patients had cardiovascular deaths.

Measurements: All-cause mortality; respiratory and cardiovascular deaths; and exposure to COPD medications, inhaled corticosteroids, ipratropium, long-acting β-agonists, and theophylline in the 6 months preceding death.

Results: Adjusted odds ratios (ORs) for all-cause mortality were 0.80 (95% CI, 0.78 to 0.83) for inhaled corticosteroids, 1.11 (CI, 1.08 to 1.15) for ipratropium, 0.92 (CI, 0.88 to 0.96) for long-acting β-agonists, and 1.05 (CI, 0.99 to 1.10) for theophylline. Ipratropium was associated with increased cardiovascular deaths (OR, 1.34 [CI, 1.22 to 1.47]), whereas inhaled corticosteroids were associated with reduced risk for cardiovascular death (OR, 0.80 [CI, 0.72 to 0.88]). Results were consistent across sensitivity analyses.

Limitations: Current smoking status and lung function were not measured. Misclassification of cause-specific mortality is unknown.


Patients were eligible for inclusion if they received a diagnosis of COPD (International Classification of Diseases, 9th Revision [ICD-9], codes 491.x, 492.x, or 496) between 1 October 1999 and 30 September 2003 at 2 or more outpatient visits within 12 months or were admitted to the hospital with a primary diagnosis of COPD. Patients had to be 45 years of age or older when they received their first eligible diagnosis, have used Veterans Health Administration health care services for at least 1 year before their first COPD diagnosis, and have received respiratory medications. We excluded patients with a diagnosis of asthma. We followed patients from the date of their second eligible outpatient visit or their inpatient visit until death or 30 September 2004.

Case Patients

We identified all deaths that occurred during follow-up by using the Veterans Affairs Vital Status database, a combination of Veterans Affairs, Medicare, and Social Security Administration mortality data that captures approximately 98% of veteran deaths. Of these, 40% was randomly sampled and we attempted to determine cause of death. This sample was estimated to provide more than 80% power to detect odds ratios of 0.85 or lower or 1.15 or higher for each medication class. We ascertained cause of death by using National Death Index Plus data from the National Center for Health Statistics. We defined 4 groups of case patients on the basis of cause of death: respiratory, cardiovascular, respiratory or cardiovascular, and all-cause mortality. We defined respiratory as death due to a respiratory system disease (ICD-10 codes J00 to J99) and cardiovascular as death due to ischemic heart disease (ICD-10 codes I20 to I25), cardiomyopathy, cardiac arrest, or arrhythmias (ICD-10 codes I42 to I51). The index date for case patients was their death date.

Control Participants

Selecting more than 5 control participants per case patient can yield limited gains in efficiency; however, because we were assessing several medications simultaneously, we selected up to 10 control participants per case patient. We randomly selected control participants for each case patient from eligible patients who were alive at the time of the case event. We matched control participants to case patients individually on the basis of sex, age category (45 to 54 years, 55 to 64 years, 65 to 74 years, 75 to 84 years, and 85 years of age), region of the country, and year of diagnosis. We assigned control participants the same index date as their matched case patients.


We defined exposure to respiratory medications as having received medications in the 180 days preceding each patient's index date. We identified medication exposure to inhaled corticosteroids, ipratropium, long-acting β-agonists, theophylline, and short-acting β-agonists. We defined primary exposure as any exposure in the 180-day period before the index date. We created mutually exclusive medication regimens on the basis of medication exposure. Exposure to short-acting β-agonists was not considered as part of the regimen but was included as a covariate in the analysis.


We identified covariates by using data from the year before diagnosis date until the index date. We used pharmacy data to identify medication use, including exposure to systemic steroids, antihypertensives, lipid-lowering medications, antiarrhythmics, and diabetes medications. We used inpatient and outpatient diagnoses to identify comorbid conditions. We measured health care utilization as the annual number of hospitalizations and outpatient physician visits. We identified COPD exacerbations during follow-up and whether they were inpatient or outpatient by using a previously described algorithm

Statistical Analysis

We performed separate analyses for respiratory-specific, cardiovascular-specific, and all-cause mortality. We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% CIs. We included the variables that we considered clinically important in each of the regression models. Specifically, we included measures of COPD-related severity in all of the models and included markers of cardiovascular disease in the models for cardiovascular and all-cause mortality. We included any remaining variables that changed OR estimates for respiratory medications by more than 10% in the final models. We assessed model fit by using the Bayesian information criterion and the Wald test of likelihood ratios and through examination of outlier effects with leverage and fit diagnostics. Adjusted odds ratios represented risk for events in patients receiving medication compared with those who had not received inhaled corticosteroids, ipratropium, long-acting β-agonists, or theophylline in the previous 6 months. We performed all analyses with Stata/MP 10.0 for Windows (StataCorp, College Station, Texas).

We conducted several sensitivity analyses to evaluate the robustness of our results. First, we restricted the comparison group to patients who were actively treated with a short-acting β-agonist in the 180 days preceding the index date. Second, because veterans may use health care services outside the Veterans Health Administration system, we restricted the analysis to patients 65 years of age or older. We used Medicare health care utilization data on these patients to capture health care utilization outside of the Veterans Health Administration system. Third, we examined dose response by classifying those in the highest quartile of average daily dose into a high-dose group and the rest of those exposed into a low-dose group. Fourth, to observe the effects of ipratropium independent of short-acting β-agonist exposure, we excluded patients who received a combination of ipratropium and short-acting β-agonists in a single inhaler. Fifth, to address the imbalance in prevalence of chronic heart failure between case patients and control participants, we created analytic cohorts by matching on presence of chronic heart failure and repeated our analyses. Finally, we used the array approach to estimate the effect that unmeasured confounding could have had on point estimates of the association between medications and mortality. We varied the level of risk associated with the unmeasured confounder and the prevalence in the medication groups relative to the no-treatment groups to determine what level of differential exposure would change the conclusions from the primary analysis. We focused on current smoking rates and COPD severity because we considered these to be 2 of the most important and influential unmeasured confounders. We compared rates of smoking status and COPD severity across treatment groups by using data from a recently published study

Results: We identified 145 020 patients who met inclusion criteria; of whom, 32 130 died . We located cause-of-death data for 11 897 patients but could not match data for 955 potential case patients. Of the patients for whom cause-of-death data were available, 2405 deaths were respiratory and 3159 were cardiovascular. Within the respiratory mortality analysis, case patients had lower rates of hypertension and osteoarthritis, higher rates of chronic heart failure, and more COPD exacerbations. Among those included in the cardiovascular mortality analysis, case patients had higher rates of cardiovascular comorbid conditions and COPD exacerbations, which suggests more severe respiratory disease. Case patients had a similar or higher prevalence of respiratory medication use than control participants. The 3 top regimens for each group were no medication or short-acting β-agonists only, ipratropium only, and inhaled corticosteroids and ipratropium.

After we adjusted for differences in covariates, both inhaled corticosteroids and long-acting β-agonists were associated with reduced odds of death (OR, 0.80 [95% CI, 0.78 to 0.83] for inhaled corticosteroids and 0.92 [CI, 0.88 to 0.96] for long-acting β-agonists), whereas ipratropium was associated with an increased risk (OR, 1.11 [CI, 1.08 to 1.15]). For cause-specific mortality, theophylline exposure was associated with a statistically significant increase in respiratory deaths compared with the unexposed group (OR, 1.71 [CI, 1.46 to 2.00]). Although point estimates indicated a more than 10% increase in the odds of respiratory death associated with long-acting β-agonists (OR, 1.12 [CI, 0.97 to 1.30]) and a more than 10% decrease with inhaled corticosteroids (OR, 0.88 [CI, 0.79 to 1.00]), neither was statistically significant. With respect to cardiovascular death, ipratropium exposure was associated with a 34% increase in the odds of cardiovascular death (OR, 1.34 [CI, 1.22 to 1.47]), whereas inhaled corticosteroid exposure was associated with a 20% decrease in the odds of a cardiovascular death (OR, 0.80 [CI, 0.72 to 0.88]). Long-acting β-agonists (OR, 0.97 [CI, 0.84 to 1.11]) and theophylline (OR, 1.16 [CI, 0.99 to 1.37]) were not associated with statistically significant risks in cardiovascular deaths.

A recently published study of veterans reported the prevalence of current smokers to be 11% among those receiving short-acting β-agonists or not treated, 20% among those receiving ipratropium, 18% among those receiving inhaled corticosteroids, and 16% among those receiving long-acting β-agonists. With current smoking associated with a relative risk for death of 1.5, these estimates would result in adjusted risk ratios of 0.77 for inhaled corticosteroids, 1.08 for ipratropium, and 0.90 for long-acting β-agonists. To reduce the association between ipratropium and all-cause mortality to an adjusted OR of 1.0, the proportion of current smokers in the ipratropium-treated group would have to reach 35% relative to the 11% observed in the no-treatment group. To reduce the association between cardiovascular death and ipratropium to an odds ratio of 1.0, the prevalence of current smoking in the ipratropium group would have had to be at least 80%.

For COPD disease severity, we assumed an increase of 1.4 in the risk for death for those with moderate to severe COPD relative to those with mild COPD, based on the NHANES (National Health and Nutrition Examination Surveys) data in Maninno and colleagues' study. From the published pilot study, we found the prevalence of moderate to severe COPD to be approximately 20% in the untreated group; 45% to 55% in those receiving inhaled corticosteroids, ipratropium, or long-acting β-agonists; and 70% in those treated for COPD. However, COPD was not newly diagnosed in the patients in this study, and the differential estimates are therefore probably higher than those for patients with newly diagnosed COPD. Accounting for severity as an unmeasured confounder would result in an all-cause mortality risk ratio of 0.90 for theophylline, 1.02 for ipratropium, 0.72 for inhaled corticosteroids, and 0.83 for long-acting β-agonists. For respiratory death, if the estimated risk for COPD-related death is increased nearly 4-fold in those with moderate to severe disease compared with those with mild disease, the risk associated with theophylline would be reduced to 0.88 if the prevalence of moderate to severe disease was 70% in the theophylline group and 20% in the no-treatment group.

Among medication regimens, those that included theophylline were associated with increased risk for respiratory death. For cardiovascular death, ipratropium alone (OR, 1.42 [CI, 1.27 to 1.59]) and ipratropium plus theophylline (OR, 1.47 [CI, 1.09 to 1.98]) were associated with increased risk, whereas the presence of inhaled corticosteroids with ipratropium reduced the risk for cardiovascular death (OR, 1.04 [CI, 0.90 to 1.22]; P < 0.001 for Wald test compared with ipratropium alone). In the all-cause mortality group, inhaled corticosteroids were consistently associated with reduced odds of death when used alone or in combination with other medications, whereas ipratropium and ipratropium plus theophylline were associated with elevated risk for death.

Conclusion: The possible association between ipratropium and elevated risk for all-cause and cardiovascular death needs further study.

Caution:   Potential confounders, such as smoking status and disease severity, were not known. Associations may not reflect causal relationships.  In addition to the risk for cardiovascular death with ipratropium, we found an increased risk for cardiovascular or respiratory death in patients exposed to theophylline that was primarily due to increased respiratory deaths. Despite limited evidence on the value of theophylline for treating patients with COPD, nearly 10% of patients received the drug. Although we attempted to control for differences in disease severity by limiting the cohort to patients with recently diagnosed COPD and by adjusting for COPD exacerbations, some of the increased risk associated with theophylline may be due to more severe disease in patients exposed to theophylline. We therefore conducted a sensitivity analysis to evaluate the influence of disease severity as an unmeasured confounder on disease outcomes. We found that the observed association between theophylline and respiratory mortality could be completely explained by differences in disease severity between the groups if the prevalence of moderate to severe disease was 60% in the theophylline-treated patients relative to 20% in the comparison group.  This was less than the 70% prevalence of moderate to severe disease that we observed among our small cohort of patients with COPD who received theophylline; however, this group was not restricted to patients with newly diagnosed COPD. Therefore, differences in disease severity may account for some of the observed difference in risk for respiratory death associated with theophylline; however, it is unclear whether a large enough difference in severity would exist among those with newly diagnosed COPD to fully explain our findings.

In contrast, we found inhaled corticosteroid use was associated with decreased risk for cardiovascular death. Our estimate of a 22% reduction in the risk for cardiovascular death, combined cardiovascular and respiratory death, and all-cause mortality in patients exposed to inhaled corticosteroids and long-acting β-agonists is consistent with the hazard ratio of 0.78 (CI, 0.57 to 1.06) reported by the TORCH trial for COPD-related deaths. Our results suggest that decreased risk for cardiovascular events may be responsible for benefits associated with inhaled corticosteroids in patients with recently diagnosed COPD. Previous reports have shown that inhaled corticosteroids reduce inflammatory markers in patients with COPD; a hypothesized mechanism includes potential reduction in cardiovascular risk. However, these results need to be considered in the context of other cause-specific mortality estimates. The patient-level meta-analysis that found benefit versus all-cause mortality found no association between inhaled corticosteroids and cardiovascular death (hazard ratio, 0.98 [CI, 0.59 to 1.62]), although the study was inadequately powered to address this outcome. Of note, the TORCH trial the INSPIRE study and a recently published observational study have all found an increased risk for pneumonia associated with use of inhaled corticosteroids. We did not assess the risk for pneumonia in this cohort, although it needs to be considered in relation to the mortality findings by patients and providers when making treatment decisions.   Our study has limitations. Observational studies are susceptible to bias due to confounding by indication, in which patients with more severe disease may be more likely to have events and therefore are more likely to be exposed to the treatment of interest. We attempted to minimize concerns about this effect by focusing on recently diagnosed disease and by controlling for markers of disease severity. In addition, we conducted a sensitivity analysis to examine the potential effect of unmeasured confounding due to disease severity. In a small sample of veterans with COPD, we found a substantial difference in the proportion of patients with moderate to severe COPD between those who received only short-acting β-agonists or no treatment and those who received other treatments. If this difference in severity was present in our study, it would have been sufficient to explain the observed increase in risk for respiratory death associated with theophylline. Severity of COPD as an unmeasured confounder could have also reduced the association between ipratropium and all-cause mortality to 1.02. However, this cohort included patients with prevalent COPD and probably overestimates the difference in the prevalence of severity by treatment group. We found that for unmeasured severity to fully account for the observed differences, the prevalence of severe disease in patients treated with theophylline would have to be 3 times that observed in those who received no treatment or who received only short-acting β-agonists. For the association between all-cause mortality and ipratropium, the prevalence of severe disease in the ipratropium group would need to be nearly 2.5 times that observed in the patients who received no treatment or who only received short-acting β-agonists. Thus, differences in severity between treatment groups would need to be very large to account for the associations that we observed.

Similar to disease severity, we could not ascertain smoking status among our cohort, which may have introduced unmeasured confounding. However, it is probable that many of these patients have a history of substantial smoking, given the clinical diagnosis of COPD. Our sensitivity analysis of current smoking rates indicates that current smokers would have to account for a larger proportion of those treated with ipratropium to reduce the odds ratio to 1.0 for either all-cause mortality or cardiovascular death. We also conducted several other sensitivity analyses that strengthen our findings due to the consistency of the results. We found consistent results across the subgroups of patients for each of the analyses.

Our study is probably underpowered for many of the medications examined in the regimen-based analysis of cause-specific mortality. Because of the low rates of exposure to some regimens, we are unlikely to find statistically significant differences. However, for the most commonly used medications, we found risks consistent with the main effects observed for each medication. We also found that combinations of medications may reduce the risks associated with individual medication exposures. In addition, many of the point estimates for the regimen-based analyses of cause-specific mortality were consistent with the all-cause mortality analysis, in which the larger number of included case patients alleviated problems of statistical power.

Our results are most applicable to men with recently diagnosed COPD and may not apply to patients with more severe disease or to women. We used National Death Index Plus data to identify cause of death, which has shown high concordance with coding by trained nosologists but may not be consistent with adjudicated deaths in clinical trials. The TORCH trial investigators observed 52% agreement between adjudicated deaths and the site investigator's coding of primary cause of death, and agreement increased to 67% compared with either primary or secondary cause listed by the site investigator. How adjudicated deaths would relate to underlying cause defined in National Death Index Plus data is unclear and thus it is difficult to know how often the cause of death we identified by using death certificate data would differ from that ascertained by an adjudication committee. The degree of misclassification may be related to severity—patients with more severe disease were more likely to have COPD listed as a cause of death. This may raise concerns that individuals treated with ipratropium had less severe disease than other patients and were more likely to be classified as having a non–COPD-related cause of death. However, we also evaluated the association between medication exposure and all-cause mortality. If the relationship between ipratropium and cardiovascular death occurred because deaths were more likely to be classified as cardiovascular than respiratory in the ipratropium group owing to differences in disease severity rather than to medication exposure, we would expect to find no association between ipratropium and all-cause mortality. However, we found an association between ipratropium and all-cause mortality, which warrants concerns about the safety of the medication in treating COPD.

Our study contributes important new evidence on the potential harms associated with medications used in COPD. Ipratropium may increase the risk for cardiovascular death; however, this risk may be attenuated by the concomitant use of inhaled corticosteroids, which were associated with reduction in the risk for all-cause and cardiovascular death. The risk for death due to some medications must be weighed against potential benefits of these medications that are not captured in observational database studies, such as symptom relief, health status, or quality of life. It is not clear, however, that these benefits would outweigh the increased risk for death. Given the risk observed in our study and in previous studies of ipratropium, caution is warranted in the use of ipratropium alone in patients with recently diagnosed COPD. It is also important to further examine this relationship through measurement of cardiovascular events and to measure the effect of such factors as disease severity and smoking status.

Grant Support: By the U.S. Department of Veterans Affairs Health Services Research and Development (IIR 03-307).

Potential Financial Conflicts of Interest: Honoraria: T.A. Lee (AstraZeneca, Novartis), D.H. Au (GlaxoSmithKline). Consultancies: K.B. Weiss (Merck & Co.). Stock ownership or options (other than mutual funds): D.H. Au (Pfizer). Grants received: T.A. Lee (Altana, Aventis, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck & Co., Novartis, Pfizer, Schering-Plough, Sepracor, University of Kentucky). Other: D.H. Au (Assessing the Impact of Recent Updates for Advair and Serevent Special Issues Board).

Those who have a financial interest in the outcome manipulate the results