Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Xigris (Eli Lilly)
5 mg and 20 mg vials
Approved indication: severe sepsis
Australian Medicines Handbook section 7
Protein C is involved in the inactivation of the coagulation cascade. The activated form of protein C has an antithrombotic effect and a deficiency of protein C can lead to thrombosis (see 'Investigations for thrombotic tendencies' Aust Prescr 1999;22:63-6).
In serious infections inflammatory cytokines can trigger coagulation, so activated protein C has an important role in modulating the procoagulant effect of inflammation. Patients with severe infections may be unable to activate protein C and those with low concentrations of protein C have a poor prognosis. Trials have therefore investigated whether adding an infusion of recombinant activated protein C (drotrecogin) to the treatment of these seriously ill patients will improve their outcomes.
A multinational double-blind trial enrolled 1690 patients with severe sepsis causing dysfunction of at least one organ system. The 850 patients given drotrecogin were compared with 840 patients who received an infusion of saline for 96 hours. One month after the infusion 25% of the patients given drotrecogin were dead. This outcome was significantly better than for the placebo group as 31% of those patients died.1
The danger of giving a recombinant anticoagulant is bleeding. One in four patients given drotrecogin had some bleeding and 3.5% had a serious haemorrhage. Two patients died of intracranial haemorrhage during the infusion.1 Drotrecogin is contraindicated in patients with a recent history of brain or spinal surgery, head trauma or haemorrhagic stroke. Patients with a bleeding tendency or peptic ulceration are particularly at risk of serious haemorrhage.
There is no antidote to drotrecogin, but as the half-life of endogenous activated protein C is relatively short, stopping the infusion will reduce the concentration within a few hours. In most patients the drug is undetectable two hours after the end of the infusion.
The clinical trialists concluded that one life would be saved for every 16patients treated with drotrecogin. However, the patients have to be carefully selected to achieve this benefit. Many patients with a potential risk of bleeding were excluded, for example, patients who had taken warfarin or more than 650mg of aspirin. Drotrecogin is likely to be expensive.
- Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.