The withdrawal of Activated Protein C from the use in patients with severe sepsis and DIC [Amendment to the BCSH guideline on disseminated intravascular coagulation]

In 2009, the British Committee for Standards in Haematology (BCSH) published guidelines on the diagnosis and management of disseminated intravascular coagulation (DIC) with recommendations for the use of activated protein C (APC, drotrecogin alfa, marketed as Xigris), in patients with severe sepsis and DIC (Levi et al, 2009). These need reconsideration in the light of recent study results and the announcement by the manufacturers of APC, Eli Lilly (Basingstoke, Hampshire, UK) to withdraw the agent from commercial use. The first major publication on the use of APC in severe sepsis was the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. Although it was designed to enroll 2280 patients, at second interim analysis after the recruitment of 1520 patients, a significant decrease in mortality (6·1%) was noted in the APC group compared with the placebo group (Bernard et al, 2001). Sub-analysis demonstrated the limitation of the benefit to patients who were more severely ill [Acute Physiology and Chronic Health Evaluation (APACHE) II scores of 25 or higher] where the absolute reduction in mortality was 13% (19% with placebo). Indeed patients with DIC had the highest benefit from APC and this was further confirmed by the observations where this agent was noted to normalize coagulation activation during severe sepsis (Dhainaut et al, 2004; de Pont et al, 2005). Based on these data, the BCSH guideline recommended the use of APC in patients with severe sepsis and DIC (grade A, level Ib) (Levi et al, 2009). The next major study, the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) was designed to examine the role of APC in those with severe sepsis and a low risk of death. This did not show any significant difference in mortality [APC group (18·5%) v/s placebo (17%) (P = 0·34)] (Abraham et al, 2005). Interestingly, the sub-analysis of the patients with APACHE II scores of 25 or higher had 28-day mortality of 29·5% compared to 24·7% with placebo. In paediatric patients, the RESOLVE (Researching Severe Sepsis and Organ Dysfunction in Children: A Global Perspective) study also showed no benefit for APC but an increased incidence of intracranial bleeding was observed (Nadel et al, 2007). This increased bleeding risk was also noted in the ENHANCE (Extended Evaluation of Human Recombinant Activated Protein C) open-label study (6·5% serious bleeding and 1·5% intracranial hemorrhage) and the Italian Ministry of Health trial (4·6%) prompting warnings to physicians to not use APC in those who had a high bleeding risk (Vincent et al, 2005; Bertolini et al, 2007; Sweeney et al, 2009). The BCSH guideline recommended against APC administration in thrombocytopenic patients and those at high risk of bleeding. With the increasing uncertainty about efficacy and the concerns about bleeding risk, the Committee for Medicinal Products for Human Use section of the European Medicines Agency (EMA) called for re-examination of the risk/benefit profile of APC. An industry-sponsored (Eli Lilly) placebo-controlled trial, named PROWESS–SHOCK, was commenced with a primary objective of assessing all-cause mortality at 28 days. At the recent completion of the PROWESS-SHOCK trial involving 1696 patients, preliminary analyses showed a 28-day all cause mortality rate of 26·4% in APC-treated patients compared to 24·2% in placebo-treated patients with a relative risk of 1·09; 95% confidence interval (0·92, 1·28), and P-value = 0·31 (not statistically significant) (http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2011/10/WC500116970.pdf). The study also failed in its secondary endpoint to demonstrate a reduction of mortality in the population of patients with severe protein C deficiency. The risk of severe bleeding events was 1·2% in the APC arm and 1·0% in the placebo arm, suggesting there was no increased harm. Following this, Eli Lilly has decided to withdraw the product from the market worldwide and both the EMA and the US Federal Drug Administration Agency have advised physicians not to initiate treatment with APC in new patients and to stop ongoing treatment. In this context, the fate of the APROCCHS (Activated Protein C and Corticosteroids for Human Septic Shock) trial started in 2010 to evaluate APC in combination with low-dose corticosteroids for the management of septic shock is under question, especially as a meta-analysis concluded no benefit for APC in septic shock (Marti-Carvajal et al, 2008, http://clinicaltrials.gov/show/NCT00625209). In view of the above we hereby withdraw the recommendations given by the BCSH guideline (Levi et al, 2009) on the use of APC in DIC. Drs Thachil and Watson and Professors Toh and Levi composed and agreed on the content of this letter which relates to the guideline that they previously authored.