We also found that IB use was associated with cardiovascular events to more or less the same extent as BA. This was not entirely unprecedented; a large clinical trial comparing IB with placebo in mild COPD noted increased cardiovascular morbidity and mortality of borderline significance in the group assigned IB, and a particularly suggestive increase in the incidence of SVT (Anthonisen et al 2002
). This was consistent with the vagolytic nature of the drug if it was absorbed (Coleman et al 1975
), and arrhythmias appear to be the most credible mechanism for IB to cause cardiovascular events. Other studies associating IB with excess mortality (Guite et al 1999
; Rigbaek and Viskum 2003
) suffered from potential confounders in that IB use was associated with disease severity and/or the diagnosis of COPD as opposed to asthma. Using a very large database, Sin and Tu (2000)
did not find and association between IB and mortality in COPD patients after adjustment for potential confounders.
The strength of any conclusions in regard to our data depends on the validity of our approach. Our database is inclusive and detailed. It included all residents of Manitoba: approximately 1.1 million people. We were able to enumerate claims for hospitalization, physician visits and all respiratory medications received by each subject with bronchitis, COPD or asthma. We attempted to control for disease severity and for cardiac and non-cardiac co-morbidities. As with all database studies, this had several important weaknesses. We cannot be certain of the accuracy of the diagnoses we were concerned with, though the accuracy of diagnosis of ischemic heart disease and COPD has been reported from a similar database (Curkendall et al 2006
); agreement between databases and survey results is at best “moderate” in chronic diseases such as asthma (Huzel et al 2002
). In the absence of laboratory data, we used proxies such as other drugs and physician visits to assess severity. We equated drug use with drug dispensing, and did not know whether patients actually used the medications that they received, though drug effects were most prominent in the 60 days after drug prescriptions, when it was reasonable to assume that the drugs were actually used. Although we adjusted for co-morbidities, such adjustments are approximations. We limited our analyses to first hospitalization for a cardiovascular diagnosis, thereby avoiding the weakness that pharmacy-derived drug databases do not enumerate drugs administered to hospitalized patients.
An alternative explanation for our results would be that bronchodilator use reflected severity of obstructive lung disease in a way that was not captured by our other measurements such as physician visits. There is excellent evidence that cardiovascular events are common in COPD and that this relates to the degree of airways obstruction (Sin and Man 2003
; Sin et al 2005
). Arrhythmias have been documented as common in patients with severe COPD (Hudson et al 1973
; Kleiger and Senior 1974
), though it was likely these assessments were made in patients who were being treated with beta agonists. We cannot definitively refute the argument that bronchodilators were simply a marker of disease severity and this accounted for their association with cardiovascular disease, but we think it unlikely for two reasons. First, use of ICS was not associated with these outcomes. ICS are recommended only in severe COPD as opposed to bronchodilators, recommended in all symptomatic cases. Cardiovascular risk was associated with bronchodilators, and not ICS, also markers of COPD severity. Further, the association of bronchodilators with cardiovascular outcomes was present in patients whose only diagnosis was bronchitis, a group with relatively few markers of disease severity such as physician visits and respiratory hospitalizations.
Odds ratios for first hospitalization due to heart failure
People who had cardiovascular events were more likely to be taking cardiac drugs than those who did not ( and ), as was expected. Of some surprise was the finding that there were significant interactive effects between bronchodilators and cardiac drugs taken as a whole (); in all cases cardiac drugs decreased the likelihood of cardiovascular events associated with bronchodilators, especially IB. The example of stroke was especially striking; on the whole bronchodilators did not increase stroke risk after adjustment for confounders, but risk was apparently dependent upon precognition of cardiovascular disease, since it was increased in those on bronchodilators who were not taking cardiac drugs. Specific drug interactions supported this interpretation (); in each case the receipt of specific cardiac drugs decreased the likelihood of hospitalizations associated with bronchodilator. A particularly notable example of this kind of drug interaction was the fact that bronchodilators did not increase the risk of arrhythmia in the presence of anti-arrhythmic agents. Bronchodilators apparently impose a larger relative risk in people with unrecognized cardiovascular disease than in people with known disorders.
Odds ratios for first hospitalization due to myocardial infarction
As noted above, ICS were not associated with cardiovascular events. Indeed, they appeared to be protective, an effect that was occasionally significant. We have previously shown in a similar cohort that ICS were associated with reduced cardiovascular mortality as compared to patients taking bronchodilators in the absence of ICS (Macie et al 2006
). It is possible that the beneficial effect of ICS is dependent upon reduction of cardiovascular events associated with bronchodilator therapy, since ICS are seldom used in the absence of bronchodilators.