XIGRIS: A novel agent in severe sepsis

Dr Atul Kothari

Xigris (drotrecogin alfa activated) was introduced in India in October 2002 by Eli Lilly, marketed aggressively as a biological agent for use in severe sepsis. Xigris is recombinant human activated Protein C that has antithrombotic, anti-inflammatory and profibrinolytic properties. The sepsis cascade is associated with simultaneous activation of systemic inflammation and coagulation, leading to microvascular endothelial injury, acute organ dysfunction and possibly death.

Various studies suggested that activated Protein C may be an important modulator in this vicious cycle of coagulation and inflammation associated with the sepsis syndrome, which if unchecked may ultimately lead to death. A large international multicentre, randomised, double blinded placebo controlled trial (PROWESS) was conducted, the results of which were published in 2001 in the New England Journal of Medicine.

In the PROWESS trial conducted in 1690, Xigris was associated with a six per cent reduction in mortality as compared with placebo in patients with severe sepsis. It was associated with an increased risk of serious hemorrhage during the recommended four day infusion period. It was claimed that for the first time, a recombinant biological had altered mortality in sepsis. This was not promoted as an alternative to antimicrobials, but as an additional agent to control the inflammation and coagulation cascade in the sepsis syndrome.

Xigris was subsequently approved by the FDA for use in patients with severe sepsis, as determined by APACHE II scores of >25 (a score designed to assess risk of mortality based on Acute Physiology and Chronic Health Evaluation).

The potential for such an agent would seem immense, however several issues regarding the interpretation of data in the PROWESS trial and appropriate use of the drug were subsequently raised. It has come to light that the investigators, halfway through the trial had changed the trial entry criteria. The master cell bank from which the activated Protein C was sourced was also changed at the same point, allegedly without an effect on drug properties. There is no laboratory test which can predict the efficacy of future lots, though Eli Lilly claims to have sufficient stores of the current master cell bank to cover several decades of activated Protein C production.

Midway into the trial, it was seen that the number of “do not resuscitate” orders documented on control patients far exceeded the number of such orders in patients receiving the trial drug. Concerns were also raised that the incidence of intracranial hemorrhage and serious bleeding may have been underestimated in patients receiving the drug.

The trial talked about a six per cent decrease in 28 day mortality in patients given Xigris, yet this difference does not appear to have carried over in hospital discharges. This would mean that while six per cent reduction in mortality was seen, it hasn’t been revealed whether these six per cent patients were actually discharged from hospital at a future point in time.

Most tellingly, where patients with APACHE II scores < 25 were given the drug, there was an actual increase in mortality compared to the control group.

This leads to the vexing issue of cost (>Rs 400,000 per course of 4 day infusion period depending on patient characteristics). In this regard, it should be noted that the numbers needed to treat to save one life, even accepting trial figures, is 16 - so effectively the cost to save one life is Rs 64,000,000.

On balance, there seem to be substantial unanswered questions about the study to preclude the use of Xigris in the management of patients with sepsis, regardless of the price of the drug. At the request of the FDA, Eli Lilly has made extensive commitments to conduct controlled trials involving more than 13,000 patients to further investigate the correct use of Xigris. A successful outcome of these trials would constitute a major advance and would settle the current controversy.

The writer is a clinical microbiologist with Max Deviki Devi Heart and Vascular Institute. Email: atul.kothari@maxhealthcare.com