Drotrecogin Alfa (Activated)

Drotrecogin Alfa (Activated) - Protein C is synthesised by the liver and activated by thrombomodulinbound thrombin to exert anti-inflammatory, anti-thrombotic and anticoagulant properties. Drotrecogin alfa (Xigris) is a recombinant activated protein C indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care (PROWESS study N Engl J Med 2001; 344: 699–709).Treatment should be started within 48 hours, and preferably within 24 hours, of onset of the first documented sepsis-induced organ dysfunction. The recommended dose of Xigris is 24 μg/kg/h given as a continuous intravenous infusion for a total duration of 96 hours. No dose adjustment is required in adult patients with severe sepsis with regard to age,  gender, hepatic or renal function.

Since its introduction, two further randomised controlled trials have been published, one in children (Lancet 2007; 369: 836–43) and the other in adults at low risk of death (N Eng J Med 2005; 353: 1332–41). Both were stopped early on grounds of inefficiency. In addition, the calculated risk of serious haemorrhage from Xigris has increased progressively with accumulating clinical experience. Overall, whether the risks of Xigris outweigh the benefits is now far from clear, even in patients with a high risk of death.

Uses:
Severe sepsis with multiple organ failure

Contraindications:
Active internal bleeding; patients at increased risk for bleeding; platelet count < 30 000 X 106/l, even if the platelet count is increased after transfusions; known bleeding diathesis except for acute coagulopathy related to sepsis; any major surgery; patients with epidural catheter; history of severe head trauma; gastrointestinal bleeding within 6 weeks; trauma patients at increased risk of bleeding
Patients with intracranial pathology; neoplasm or evidence of cerebral herniation; haemorrhagic stroke within 3 months; A-V
Malformations
Concurrent heparin therapy >15 International Units/kg/h
Chronic severe hepatic disease

Administration
Recent evidence from the XPRESS study suggests that thromboprophylactic doses of unfractionated heparin or low molecular weight
heparin should not be stopped when drotrecogin alfa is prescribed, as a rebound effect appears to occur.
Haemofiltration: if the patient requires haemofiltration while receiving drotrecogin alfa, no addition anticoagulation is usually required.

How not to use drotrecogin alfa:
Xigris should not be used in patients with single organ dysfunction or a low risk of death (e.g.APACHE II score <25), or in children.

Adverse effects:
Bleeding
• Serious bleeding events during the infusion period
   Incidence of serious bleeding events 2.4%
   Incidence of CNS bleeds 0.3%
   Recent surgery was associated with a higher risk of serious bleeding
• Serious bleeding events during the 28-day study period
   Incidence of serious bleeding events 3.5%
   Incidence of CNS bleeds 0.2%

Cautions:
Recent administration of thrombolytic therapy, oral anticoagulants, aspirin or other platelet inhibitors, or recent ischaemic stroke, the risks of the administration of Xigris should be weighed against the anticipated benefits. No observed increase in the risk of bleeding events was reported as serious adverse events in drotrecogin alfa (activated) patients receiving prophylactic doses of unfractionated or low molecular weight heparin

For procedures with an inherent bleeding risk, discontinue Xigris for 2 hours prior to the start of the procedure. Xigris may be restarted 12 hours after major invasive procedures

If sequential tests of haemostasis (including platelet count) indicate severe or worsening coagulopathy, the risk of continuing the infusion
should be weighed against the expected benefit Xigris should not be used during pregnancy or lactation unless clearly necessary

Organ failure:
Renal: no dose adjustments required
Hepatic: no dose adjustments required