CONFOUNDING BY SEVERITY DOES NOT EXPLAIN THE ASSOCIATION BETWEEN FENOTEROL AND ASTHMA DEATH

Three recent case-control studies from New Zealand, and one from Saskatchewan, Canada, have found that fenoterol increases the risk of death in patients with severe asthma. It has been suggested that these findings may be due to confounding by severity, if fenoterol was selectively prescribed to more severe asthmatics. This 'confounding by severity' hypothesis has now been investigated in further analyses of data from the New Zealand case-control studies. This analysis found that among patients whose asthma was severe enough to require hospital admission (the population in whom the case-control studies were conducted), fenoterol was not preferentially prescribed to the more severe asthmatics. There was greater co-prescribing of other drugs with fenoterol (compared with salbutamol) during the later years of the epidemic, but these differences did not explain the excess risk associated with fenoterol, and there was little evidence of greater co-prescribing during the earlier years of the New Zealand epidemic of asthma deaths. There was no association between the prescription of fenoterol and markers of acute asthma severity or psychosocial problems. Patients were not selectively changed to fenoterol as a result of a severe attack resulting in a hospital admission. Most importantly, in the case-control studies of asthma deaths, the inhaled fenoterol relative risk increased when the analysis was restricted to sub-groups defined by markers of chronic asthma severity; whereas the relative risk would have decreased towards 1.0 in these sub-group analyses if the overall elevated risk for fenoterol was due to confounding by severity. We conclude that in patients whose asthma is severe enough to require hospital admission, there is little evidence that fenoterol was selectively prescribed to the more severe patients and that the findings in the most severe sub-groups effectively exclude the 'confounding by severity' hypothesis as an explanation for the recent case-control findings.