Grade A Recommendation
Activated protein C (Xigris) for the treatment of severe sepsis in adults.
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Author info
Posted By: Gordon S. Doig
Posted Date: 20 Sep 2007
Title: Activated protein C (Xigris) for the treatment of severe sepsis in adults.
PubMed Resource Link: Click here to repeat the Medline search used to develop this EBR.
Evidence-based Recommendation
Best level of evidence
Well conducted Level I RCT.
Target Population
Patients with a known or suspected infection (Table 1) on the basis of clinical data who meet the following criteria within a 24-hour period:
1) three or more signs of the Systemic Inflammatory Syndrome (SIRS, Table 2) and
2) the sepsis-induced dysfunction of at least one organ or system (Table 3) that has lasted no longer than 24 hours

Table 1. Patients had to have a known or suspected infection, as evidenced by one or more of the following:

  • white cells in a normally sterile body fluid;
  • perforated viscus;
  • radiographic evidence of pneumonia in association with the production of purulent sputum;
  • a syndrome associated with a high risk of infection (e.g., ascending cholangitis).

Table 2. Patients had to meet at least three of the following four SIRS criteria:
  • a core temperature of ≥ 38 C (100.4 F) or ≤ 36 C (96.8 F);
  • a heart rate of ≥ 90 beats/min, except in patients with a medical condition known to increase the heart rate or those receiving treatment that would prevent tachycardia;
  • a respiratory rate of ≥ 20 breaths/min or a PaCO2 of ≤ 32 mm Hg or the use of mechanical ventilation for an acute respiratory process;
  • a white-cell count of ≥ 12,000/mm3 or ≤ 4,000/mm3 or a differential count showing > 10 percent immature neutrophils.

Table 3. Patients had to meet at least one of the following five organ dysfunction criteria:

  • for cardiovascular system dysfunction, the arterial systolic blood pressure had to be ≤ 90 mm Hg or the mean arterial pressure ≤ 70 mm Hg for at least 1 hour despite adequate fluid resuscitation, adequate intravascular volume status or the use of vasopressors in an attempt to maintain a systolic blood pressure of ≥ 90 mm Hg or a mean arterial pressure of ≥ 70 mm Hg;
  • for kidney dysfunction, urine output had to be < 0.5 ml/kg of body weight/hr for 1 hour, despite adequate fluid resuscitation;
  • for respiratory-system dysfunction, the ratio of PaO2 to FiO2 had to be ≤ 250 in the presence of other dysfunctional organs or systems or ≤ 200 if the lung was the only dysfunctional organ;
  • for hematologic dysfunction, the platelet count had to be < 80,000/mm3 or to have decreased by 50 percent in the 3 days preceding enrollment;
  • in the case of unexplained metabolic acidosis, the pH had to be ≤ 7.30 or the base deficit had to be ≥ 5.0 mmol/liter in association with a plasma lactate level that was > 1.5 times the upper limit of the normal value for the reporting laboratory.
To reduce mortality, measured at 28 days after the onset of treatment, by 6.1%.
Exclusion criteria
The following exclusion criteria were applied to patients enrolled into the Level I RCT. Clinical judgement should be exercised when applying these criteria in normal clinical practice.

Exclusion criteria:
Pregnancy or breast-feeding.
Age <18 yr or weight >135 kg.
Platelet count <30,000/mm3.
Conditions that increased the risk of bleeding:

  • surgery requiring general or spinal anesthesia within 12 hours before the infusion, the potential need for such surgery during the infusion, or evidence of active bleeding postoperatively;
  • a history of severe head trauma requiring hospitalization, intracranial surgery, or stroke within 3 months before the study or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or mass lesions of the central nervous system;
  • a history of congenital bleeding diatheses;
  • gastrointestinal bleeding within 6 weeks before the study unless corrective surgery had been performed;
  • and trauma considered to increase the risk of bleeding.
Known hypercoagulable condition, including
  • resistance to activated protein C;
  • hereditary deficiency of protein C, protein S, or antithrombin III;
  • presence of anticardiolipin antibody, antiphospholipid antibody, lupus anticoagulant, or homocysteinemia;
  • or recently documented (within 3 months before the study)or highly suspected deep-vein thrombosis or pulmonary embolism.
Patient's family, physician, or both not in favor of aggressive treatment of patient or presence of an advanced directive to withhold life-sustaining treatment.
Patient not expected to survive 28 days because of uncorrectable medical condition, such as poorly controlled neoplasm or other end-stage disease.
Moribund state in which death was perceived to be imminent.
Human immunodeficiency virus infection in association with a last known CD4 count of ≤ 50/mm3.
History of bone marrow, lung, liver, pancreas, or small-bowel transplantation.
Chronic renal failure requiring hemodialysis or peritoneal dialysis*
Known or suspected portosystemic hypertension, chronic jaundice, cirrhosis, or chronic ascites.
Acute pancreatitis with no established source of infection.
Participation in another investigational study within 30 days before the current study.
Use of any of the following medications or treatment regimens:
  • unfractionated heparin to treat an active thrombotic event within 8 hours before the infusion ;
  • low-molecular-weight heparin at a higher dose than recommended for prophylactic use (as specified in the package insert) within 12 hours before the infusion;
  • warfarin (if used within 7 days before study entry and if the prothrombin time exceeded the upper limit of the normal range for the institution);
  • acetylsalicylic acid at a dose of more than 650 mg/day within 3 days before the study;
  • thrombolytic therapy within 3 days before the study ;
  • glycoprotein IIb/IIIa antagonists within 7 days before study entry;
  • antithrombin III at a dose of more than 10,000 U within 12 hours before the study;
  • or protein C within 24 hours before the study.

*Acute renal failure was not an exclusion criterion.
Prophylactic treatment with a dose of unfractionated heparin of up to 15,000 U per day was permitted.
Thrombolytic agents were permitted for the treatment of thromboses within a catheter.
Drotrecogin alfa activated was infused continuously for a total duration of 96 hours at a dose of 24ug/kg.
Patients had to begin treatment within 24 hours after they met the inclusion criteria.

N.B. - The infusion was interrupted one (1) hour before any percutaneous procedure or major surgery and was resumed one (1) hour after the percutaneous procedure and 12 hours after major surgery, in the absence of bleeding complications.

Potential harm
The incidence of serious bleeding * was marginally higher in the group receiving Xigris during the infusion period (3.5% vs 2.0%, p=0.06).

In both the Xigris and placebo group, "serious bleeding occurred primarily in patients with an identifiable predisposition to bleeding, such as GI ulceration, activated partial-thromboplastin time > 120 secs, prolonged prothrombin time (an international normalized ratio of more than 3.0), a platelet count that decreased to less than 30,000 per mm3 and remained at that level despite standard therapy, traumatic injury of a blood vessel or traumatic injury of a highly vascular organ."

* Serious bleeding was defined as any intracranial hemorrhage, any life-threatening bleeding, any bleeding event classified as serious by the investigator or any bleeding that required the administration of 3 units of packed red cells on two consecutive days.

Development Information
Date EBR last updated
20 Sep 2007
Literature source and search terms
Pubmed was searched using the term:
drotrecogin alfa activated,
which automatically maps to the appropriate MeSH substance name.
The search was performed using a 'narrow' Clinical Query for articles on Therapy.
Study selection
34 abstracts were retrieved in the initial search.
Two primary RCTs were identified and reviewed. One trial (ADDRESS) was stopped early due to futility. Due to early stopping, it cannot rule out a meaningful treatment effect in the populations studied.
  • Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis. NEJM 2001;344:699-709. (Level I)
  • Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005 Sep 29;353(13):1332-41. (Level I - stopped early due to futility)

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