Aernoud Fiolet

169 Reply. Colchicine in Patients with Chronic Coronary Disease RESPONSE The authors reply: The first three correspondents raise questions about apparent quantitative differences in treatment effect among subgroups. In general, we think that the results for the overall trial provide the most reliable estimate of treatment effect. We urge caution in interpreting the primary outcome in subgroups, since such comparisons are almost always underpowered and come with increasing statistical likelihood of false positive results. 1,2 Subgroup differences are common, and the regional differences found in our trial are unexplained by known biologic mechanisms. We are currently further exploring possible reasons for these hypothesis-generating results. We share the concern of Gebhard and Regitz-Zagrosek regarding sex-related differences in pathophysiologic features and sociocultural behavior (i.e., “gender”) among patients with coronary disease. The enrollment of women in our trial was not proportional to the prevalence of cardiovascular disease among women in the general population. This reality is in line with other trials and remains a matter of concern to funders and regulatory authorities. 3,4 Various explanations, including sex-based differences in the perception of risk in participating in a trial, have been suggested in the literature. 5 We were not able to identify reasons for the underrepresentation of women in our trial. We note that our results were directionally consistent according to region and sex and in line with the findings from the earlier COLCOT, which should give health care providers the confidence to administer the treatment in various populations. Lucijanic et al. suggest that proinflammatory effects of CHIP as mediated by the NLRP3 inflammasome could modify the treatment effects observed in our trial. The correlation of this genetic marker with clinical outcomes may identify a high- response subpopulation, but we are unable to explore this hypothesis because we currently do not have access to the required blood samples.