An update on activated protein C (xigris) in the management of sepsis.

Recombinant activated protein C (APC) (Xigris, Eli Lilly) has anticoagulant, anti-inflammatory, and fibrinolytic properties.1 In November 2001, the FDA approved the use of APC in patients with severe sepsis and at a high risk of death, defined as a score of 25 or higher in the Acute Physiology and Chronic Health Evaluation (APACHE II). At the time, the FDA also requested that additional studies be conducted by the manufacturer in children and in adults with sepsis who had a lower risk of death. In the intervening years, several studies have examined the risks and benefits of APC in patients with sepsis. This review provides an update on the use of APC since its approval. A snapshot of major studies is provided in Table 1. Table 1 Summary of Significant Studies of Activated Protein C (Xigris) EFFICACY The publication of the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial marked a significant advance in the management of patients at a high risk of death.1,2 The study was designed to evaluate the impact of APC on mortality in patients with severe sepsis. The investigators had intended to enroll 2,280 patients, but enrollment was halted after a second interim analysis of 1,520 patients revealed a significant decrease in mortality in the APC group compared with the group receiving placebo. APC was associated with an absolute reduction in mortality of 6.1%. A subset analysis showed that the mortality benefit was limited to patients who were more severely ill (APACHE II scores of 25 or higher) in whom the use of APC was associated with an absolute reduction in mortality of 13%. Conversely, APC use in patients with APACHE II scores of below 25 had a mortality rate of 19%, which was identical to that of the placebo group. Consequently, APC was labeled for use in patients with severe sepsis and a high risk of death. Despite the impressive findings of PROWESS, the FDA advisory committee raised significant concerns.3 Halfway through the study, the protocol was amended and the drug-manufacturing process was changed. The protocol changes were made to ensure that patients who were more likely to die within 28 days from causes other than sepsis would be excluded from the study. Although the intent of the amendment existed in the original protocol (i.e., to exclude patients who were likely to die from causes other than sepsis), the study’s exclusion criteria were further clarified in the amendment.4 Baseline demographics of patients in the original and amended protocols were similar. Notable differences included fewer APACHE II chronic health problems in patients in the amended protocol, more acidosis in the original group (46% vs. 26%) and higher interleukin-6 (IL-6) levels in the amended group (566 vs. 389 mcg/mL). 4 Examination of mortality rates before and after the protocol amendments suggested that the changes were beneficial (Figure 1; see page 506). Figure 1 Cumulative 28-day mortality over time. The amended version of the protocol was introduced at Line A, the first interim analysis occurred at Line B, and the second interim analysis at Line C. (From FDA briefing document, BLA #125029/0.29) Concerns over the study’s findings resulted in a vote of 10 to 10 by the FDA’s advisory group regarding APC approval.3 Statistical evaluation of mortality in the pre-amendment and post-amendment groups resulted in a P value of 0.08. 4 Although the FDA acknowledged a potential for the amendment’s effect, data showing that patients with chronic health problems derived the most benefit from the drug (even though the protocol amendment decreased enrollment of these patients) led the FDA to conclude that the differences arose by chance. The drug was subsequently approved for clinical use. Upon approval of APC, the FDA required an additional study—Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS)—to determine the drug’s efficacy in patients with severe sepsis and a low risk of death.5 The study was terminated early after 2,640 patients were enrolled because of a low likelihood of APC’s showing a beneficial effect. There was no significant difference in mortality between the APC group (18.5%) and the placebo group (17%) (P = 0.34). Within the study was a subset of 321 patients who had APACHE II scores of 25 or higher (the subgroup of patients who had benefited from APC in the PROWESS trial). Mortality rates at 28 days were 29.5% in this subgroup and 24.7% in those receiving placebo. There was no difference in mortality in patients with multiple-organ dysfunction at baseline. Data from PROWESS suggested that APC in patients with APACHE II scores of 25 or higher would result in one life saved for approximately every eight patients treated; the FDA used this information to support the approval of APC.6 The lack of benefit of APC in ADDRESS in patients with APACHE II scores of 25 or higher raised concerns about the efficacy of APC, although the number of patients was small and the patients were considered to be at low risk for death at the time of study randomization.7 It was suggested that another study of patients with sepsis and a high risk of death be conducted to confirm the benefit of APC.8–10 Finally, a follow-up subset analysis of PROWESS and ADDRESS revealed an increased risk of death in patients with single-organ dysfunction who had recently undergone surgery (within 30 days). This discovery prompted a change in the package insert to include a warning for using APC in this patient population.11 The efficacy of APC was also evaluated in pediatric patients in a study known as RESOLVE (Researching Severe Sepsis and Organ Dysfunction in Children: A Global Perspective). 12 This prospective, placebo-controlled, randomized trial enrolled children between 38 weeks and 17 years of age. After 477 subjects were enrolled, the study was terminated early because the independent monitoring committee advised that the likelihood of showing a benefit was low.13 The committee also noted an increased rate of intracranial hemorrhage in the patients receiving APC. Overall, there were 11 central nervous system (CNS) bleeding episodes in the APC group (4.6%) and five in the placebo group (2.1%) (P = 0.13). A companion editorial acknowledged the increasingly tenuous benefit of APC and reiterated the need to either definitively identify patients for whom APC was effective or pursue a definitive controlled study.14 In 2007, the European Medicines Agency stated that the risks versus the benefits of APC were unclear and called for another placebo-controlled trial to be conducted. Eli Lilly agreed to sponsor PROWESS–SHOCK. This study is currently recruiting patients with a target end date of August 2011.15 The primary objective is all-cause mortality at 28 days. A study now under way is APROCCHS (Activated Protein C and Corticosteroids for Human Septic Shock). This placebo-controlled trial is evaluating APC with and without low-dose corticosteroids for the management of septic shock.16 A meta-analysis on the use of APC for severe sepsis, from 2008, concluded that there was no evidence to support the use of APC for managing severe sepsis or septic shock.17 The meta-analysis included four studies involving 4,911 patients (4,434 adults and 477 children). 2,5,12,18 The investigators recommended a moratorium on the use of APC until additional randomized controlled trials showed a benefit of therapy. The need for PROWESS–SHOCK and APROCCHS is a strong indicator that a state of clinical equipoise has been reached in terms of using APC for sepsis. With more than 200 centers participating in these placebo-controlled trials, it is evident that a significant segment of the critical-care community is uncertain about the role of APC. Thus, more robust evidence is needed before APC is adopted as the standard of care for sepsis.