Alfa ( Activated ) Administration : Too Many Subgroups To the

It is always very dangerous to look at many subgroups in a trial, even a positive one. Although those decisions were logical, it is precisely what both the Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products have done when licensing activated protein C (Xigris) only in the most severe patients. Acute Physiology and Chronic Health Evaluation II score 25 and multiple organ failures were used, respectively, by the Food and Drug Administration and European Agency for the Evaluation of Medicinal Products to select the most appropriate patients for the drug usage. The recent paper from Dr. Ely and colleagues (1) provides important information on those different subgroups but also raises many unsolved issues. The first main problem is that there is a poor consistency in the results of the different groups selected with the different markers of “low severity” analyzed in the paper. For example, the effect of the drug is striking in the first interleukin-6 quartile (lowest levels) and far lower in the three upper quartiles (no effect at all in the second one), although interleukin-6 levels should be correlated, at least in part, with severity. Similarly, the effect of the drug is surprisingly more important in the first Sequential Organ Failure Assessment quartile than in the three other ones. The multivariate logistic regression performed in the placebo group allowed the authors to calculate a predicted risk of mortality, and it represents the most innovative piece of information of this paper. Unfortunately, the effect of the drug is not correlated with this mortality risk index. In particular, there is no effect at all in the 317 patients with a risk of mortality between 20% and 30% (in contrast with what is mentioned in the summary), and obviously the difference between placebo and treated patients appears, as mentioned in the discussion section, only above a predicted mortality rate of 30% (753 patients). The second concern is that there is no relationship between the effect of the drug and the importance of protein C deficiency. On the contrary, the effect of the drug is more evident in the group without protein C deficiency, even if the confidence interval crosses one, in this small group of 196 patients. Finally, and even more important, no data are provided on the comparability of the placebo and treated arms in patients with an Acute Physiology and Chronic Health Evaluation II 25 and with more than one organ system failure. Small and insignificant imbalances in the incidence of preexistent diseases (but apparent for every of those, except hypertension) were already worrisome in the pivotal paper from Bernard et al. (2). Due to the absence of any global score assessing the “past” of the patient (like McCabe or ASA), which have been shown to be independent prognostic factors (3), it was not possible to compare the two groups in this respect other than looking at imbalances in each of those underlying diseases. The striking difference in mortality rate induced by the drug in patients with an Acute Physiology and Chronic Health Evaluation score 25 could very well be due to more pronounced imbalances between the two arms in this subgroup, in particular concerning age and underlying diseases. This happened in the past for other compounds (4, 5). It is surprising that both North American and European agencies agreed to license the drug without asking for this information.