New Treatment for Severe Sepsis on the Horizon

Abstract & Commentary

Source: Bernard GR, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.

Severe sepsis with acute organ dysfunction is thought to result from a generalized inflammatory and procoagulant host response to an infection. Endogenous activated protein C is an important modulator of these responses. Reduced levels of protein C are found in the majority of patients with sepsis and are associated with an increased risk of death. This randomized, double-blind, placebo-controlled, phase III trial was conducted to determine whether the administration of recombinant human activated protein C would reduce the rate of death from all causes at 28 days in patients with severe sepsis.

Patients with systemic inflammation and organ failure due to acute infection were enrolled and randomized to receive an intravenous infusion of either placebo or recombinant human activated protein C for 96 hours. Eligibility criteria were extensive, but essentially, patients were included who had known or suspected infection, clinical findings of a predefined systemic inflammatory response syndrome, and one or more organs with sepsis-induced dysfunction. There were numerous exclusion criteria, including, but not limited to: conditions that increase the risk of bleeding, known hypercoagulable conditions, history of a major organ transplantation, chronic renal failure requiring hemodialysis or peritoneal dialysis, cirrhosis, and chronic ascites.

Baseline demographic and severity of disease indicators were similar in the two groups, as were the sites and causes of infection and indicators of coagulation and inflammation. There were 840 patients treated in the placebo group and 850 in the activated protein C group, with 28-day mortality rates of 31% and 25%, respectively (P = 0.005). Treatment with activated protein C was associated with a reduction in the relative risk of death of 19% (95% CI, 6.6-30.5). A consistent reduction in the risk of death in patients treated with activated protein C was noted among subgroups, including the subgroups with protein C deficiency and normal protein C levels. The incidence of serious bleeding was higher in the activated protein C group than in the placebo group (3.5% vs 2.0%; P = 0.06).

Comment by Stephanie B. Abbuhl, MD, FACEP

The authors comment in their discussion that, in similar sepsis patients, one life would be saved for every 16 patients treated with activated protein C. Despite that one serious bleeding event could be expected for every 66 patients treated (and most patients with a higher risk of bleeding were excluded), these are rather impressive results. The trial was sponsored by Eli Lilly, but the study design and analysis were well done and the results are promising. There are rumors of probable Food and Drug Administration approval for the as-of-yet-unnamed Lilly drug as early as August 2001. The pharmacy department in our hospital is already concerned about the impact this drug may have on its budget, given expectations that a course of therapy may cost thousands of dollars.

It appears that the biologic activity of activated protein C is at least partly a result of its inhibition of thrombin by inactivating factor Va and VIIIa. This is consistent with the finding that the patients who received the activated protein C had significantly greater decreases in plasma D-dimer levels than the patients who received placebo. Activated protein C also appears to work by decreasing inflammation. This was supported by the finding of significantly decreased interleukin-6 levels in the activated protein C group.

In the near future, there is a good chance we will be treating patients in the emergency department with activated protein C for severe sepsis. Two things will be important for us to consider as we try to decide who to treat with this expensive new drug: First, how much should we (or will we) deviate from the extensive exclusion criteria in the study, and what will the serious bleeding complication rate be in those patients? I suspect it will be significantly higher. Second, how much should we deviate from the inclusion criteria to treat patients with sepsis that is less than severe? It is interesting to note that at the time of initial treatment, more than 70% of the patients were in shock and 75% were already on mechanical ventilation. It is going to be difficult to make some of these decisions based on the limited data we have and in light of the substantial cost that this new therapy probably will incur.