To the Editor: In their editorial on the rofecoxib controversy, Langton et al point out that large-scale but inconclusive studies failed to recognise an increased risk of heart attack and stroke in patients treated with this cyclooxygenase 2 (COX-2) inhibitor.1 Might something still be learned from these studies? Both COX-2 and 5-lipoxygenase (5-LOX) use the same substrate (arachidonic acid) to produce prostaglandins and leukotrienes, respectively. Overactive 5-LOX increases the risk of heart attack and stroke,2,3 and may be involved in the comorbidity of these disorders with anxiety and depression.4 In contrast, COX-2 appears to be cardioprotective. 5

Genetic diversity is responsible for overactive 5-LOX in some individuals and increases their risk for cardiovascular pathology.2,3 It is likely that patients with these alleles might be more susceptible to cardiovascular pathology in the absence of COX-2 activity — that is, be at increased risk of rofecoxib-provoked myocardial infarction and stroke.

If possible, retrospective studies should be attempted to determine the genotype of subjects treated with rofecoxib for 5-LOX2 and 5-LOX-activating protein3 polymorphisms and to relate these findings to rates of myocardial infarction and stroke.