The results of Studies 1 and 2 do not provide evidence of benefit of Xigris in patients with severe sepsis who are not at high risk of death (e.g., patients with single-organ dysfunction or APACHE II score < 25). Xigris is not indicated for such patients.

Study 3 (Pediatric Study)

A randomized, double-blind, placebo-controlled trial of Xigris (96-hour infusion at 24 mcg/kg/hr) was conducted in 477 pediatric patients with severe sepsis (age limits ≥ 38 weeks corrected gestational age to < 18 years). Patients were required to have both sepsis-induced cardiovascular and respiratory organ dysfunction (defined as treatment with vasoactive agents despite adequate fluid resuscitation and invasive mechanical ventilation).

The study was stopped after a planned interim analysis showed Xigris was unlikely to show statistically significant improvement over placebo in the primary efficacy measure, a composite endpoint based on time to resolution of organ dysfunction (cardiovascular, respiratory, and renal), incorporating also unresolved organ dysfunction and mortality.

Central nervous system bleeding occurred in a greater number of Xigris-treated patients during the 28-day study period; this difference was most pronounced in patients aged 60 days or younger ( ≤ 60 days: 4/24 Xigris-treated patients versus 0/26 placebo-treated patients; > 60 days: 7/216 Xigris-treated patients versus 5/211 placebo-treated patients).

All-cause mortality at 28 days, all serious bleeding events, all serious adverse events, fatal CNS bleeding events, and major amputations were similar in the Xigris and placebo groups. The results of this study do not provide evidence of benefit of Xigris in pediatric patients with severe sepsis.

Study 4 (Heparin Study)

A randomized, double-blind, placebo-controlled trial (XPRESS) investigated the safety of prophylactic heparin when concomitantly administered with Xigris (96-hour infusion at 24 mcg/kg/hr) in adult patients with severe sepsis who were at high risk of death (n=1935).

Patients were randomized 1:1:2 to receive low molecular weight heparin enoxaparin (40 mg every 24 hours), unfractionated sodium heparin (5000 U every 12 hours), or placebo administered concomitantly with the Xigris infusion. Outside the Xigris treatment period (prior to study entry and following Xigris infusion), the use of commercially available heparin was left to the discretion of the investigator.

The 28-day all-cause mortality was similar between heparin and placebo groups: individual heparin groups combined 28.2% (275/976), placebo 31.8% (305/959) (RR: 0.89, 95% CI: 0.77-1.02). There were no significant differences between the heparin and placebo groups in the rate of either venous thrombotic or serious bleeding events, including intracranial hemorrhage. Prophylactic heparin increased the risk of non-serious bleeding compared with placebo over the treatment period of 0-6 days.

In the subgroup of 889 patients receiving commercially available heparin at study entry, those patients randomized to placebo had higher mortality (placebo 35.5% (154/434) versus heparin 26.8% (122/455) and higher rate of serious adverse events (placebo 18.0% (78/434) versus heparin 11.6% (53/455) compared with patients in whom commercial heparin was replaced by study heparin (see WARNINGS). Increased serious adverse events in this subgroup included cardiac, gastrointestinal, and venous thrombotic events. In patients not receiving commercial heparin at study entry, mortality and the rate of serious adverse events were similar between heparin and placebo groups.

REFERENCES

1. Bernard GR, et al. Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis. N Engl J Med. 2001;344:699-709.

2. Knaus WA, et al. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-829.

Bookmark this page: