It is reassuring that no serious bleeding events were related to higher doses; however, http://www.selleckchem.com/products/Imatinib-Mesylate.html the numbers of patients receiving higher doses were relatively small and ultimately a larger study would be required to better quantify how bleeding relates to a higher dose and/or longer duration of DAA.As with the serious bleeding events, the overall mortality was higher in alternative therapy patients with moderate protein C deficiency. Upon distillation of the therapy groups, it can be seen that the 28-day mortality rates were similar to those seen in the DAA-treated groups from PROWESS [3] and ENHANCE [17] (24.7% and 25.3% respectively) except for patients stratified as moderately deficient in the standard paradigm, as depicted in Figure Figure4.4.

The reason for this unseemingly low mortality rate within an obviously sick group of patients is unclear. What is interesting is that in the moderately deficient groups who all received the same dose of DAA, whether patients received a shorter infusion duration, the standard infusion duration, or a longer duration of DAA (as highlighted in Table Table4,4, 28-day mortality by infusion duration), the mortality was higher in the alternative group compared to standard, which would imply that these differing mortality rates are not due to the intervention of DAA itself. It is also of note that higher mortality with alternative therapy was not seen in the severe deficiency strata, where the alternative therapy received the longest infusion durations and highest overall exposure. Most patients died of sepsis related causes, and there were no deaths thought to be related to study drug.

However, it must be remembered this is a phase 2 trial not powered for mortality and the small sample size in the alternative therapy groups renders these mortality results unreliable. Nonetheless it was disappointing that no overall trend for a mortality improvement was seen with alternative therapy. Shorter infusions of DAA have been proposed in patients based on clinical markers [18,19]. Based on the experience of this trial, we would not recommend shorter infusions of DAA.Figure 4Comparison between studies of 28-day mortality by Day 4 protein C level. Twenty-eight-day mortality is shown based on Day 4 protein C levels by categories: normal (> 80%); moderately deficient (41 to 80%); and severely deficient (��40%) …One key unique aspect of our project was the tailoring of treatment based on serial biomarker measurements. Very few studies, in either hospitalized patients or critically ill subjects, have attempted to individualize Cilengitide a therapeutic intervention based on both initial values and their sequential evaluation over time.